乙肝疫苗免疫人群隐匿性乙型肝炎病毒感染的分子与细胞免疫机制

Occult hepatitis B virus infection (OBI) appears in hepatitis surface antigen (HBsAg) negative but HBV DNA positive (HBsAg-/HBV DNA+) with low viral load or undetectable. Data indicated that OBI not only could infect the general population of blood donors, but also could partially transmit HBV to recipients by blood transfusion, and might be associated with severe liver damage and hepatocellular carcinoma，which highly attracted attentions from scientists in clinical medicine and virology. In our previous studies, we molecularly characterized the OBI strains with genotypes A1, A2, B, C, D and E from blood donors prevalent in Europe, North America, Africa and Asia, and partly described the mechanisms of OBI occurrence. We published over 20 papers in highly qualified international journals, which allowed us to lead OBI study in the world. Recently,we discovered that neonatally hepatitis B vaccinated repeat blood donors still could be newly infected with OBI. Why hepatitis B vaccination could not fully prevent the occurrence of OBI? The proposal presented here is to compare the difference in molecular and cellular immune responses among OBI carriers, HBV resolvers and HBV non-infected individuals from the vaccinated repeat blood donors, which would present the cellular immune mechanism of OBI occurrence.The predictive achievements obtained from this study would play a great significance in improvement of hepatitis B vaccination strategy, blood safety screening, and clinical therapy for HBV infection.

隐匿性乙型肝炎病毒感染（OBI）表现为乙肝表面抗原（HBsAg）阴性而HBV-DNA阳性，病毒载量低或不可定量。OBI可以通过输血传播，与重症肝损伤和肝细胞癌相关，受到病毒学及临床医学专家的高度重视。前期我们分析了全球各地区献血者人群OBI主要基因型A1、A2、B、C、D和E的分子病毒学特性，发表SCI论文20余篇，部分揭示了OBI产生的分子机制。近年我们发现，乙肝免疫人群即使在中和抗体anti-HBs>100IU/ml的有效水平，甚至在anti-HBs>300IU/ml的高水平状态下，仍可发生OBI。为什么乙肝疫苗免疫不能有效预防OBI发生呢？本课题拟针对具有高水平anti-HBs的18-24岁重复献血者人群，详尽分析新发OBI携带者、HBV感染康复者及非感染者之间的特异性分子细胞免疫反应差异，阐明OBI发生的分子与细胞免疫机制，为优化乙肝疫苗免疫策略及血液安全筛查提供理论指导。

隐匿性乙型肝炎病毒感染（OBI）是定义为一种存在肝组织或血液中乙肝表面抗原（HBsAg）阴性而HBV DNA阳性（HBV DNA+/HBsAg-）的HBV 持续性感染状态，通常病毒载量低、anti-HBc阳性而anti-HBs阳性或阴性。OBI可通过输血传播并对肝组织及其功能造成损害。本项目针对乙肝疫苗免疫献血者人群OBI状态，分析了121例OBI血液样品的分子病毒学特性，揭示了我国OBI流行株主要为HBV野生型，少量OBI毒株的Pre-S1/S2和S蛋白突变与献血者HBV中和抗体（anti-HBs）选择压力相关。该研究结果为评估OBI毒株变异及判断疫苗诱导中和抗体的保护作用和血液安全筛查方案提供了理论和技术指导。本研究还发现除HBV囊膜蛋白突变外，核心（core）蛋白关键氨基酸突变也可阻碍core蛋白合成，影响HBcAg和HBeAg生成，抑制HBV病毒复制，进而导致OBI发生。该研究结果为全面揭示OBI发生的分子机制提供了新线索。本项目建立了OBI携带者、慢性感染者（CHB）、乙肝感染康复者和未感染者四组献血者研究队列，经过详尽的跟踪检测分析，揭示了高水平IFN-γ, IL-17A及IL-21 CD4+/CD8+效应T细胞反应决定HBV康复性转归，而高水平IL-10 CD4+/CD8+抑制性T细胞反应导致HBV慢性感染进展。本研究认为OBI是介于康复性和慢性HBV感染的中间阶段，其中IL-21 效应和IL-10抑制T细胞反应起到决定HBV感染转归发展放向的关键作用。本项目成果为HBV及OBI防治提供了重要理论依据。本项目以第一标注基金课题 （No. 81871655）在Int J Infect Dis （2020）、J Hepatol（2021）和Front Microbiol （2022）三个杂志发表了上述研究成果。