不同免疫史人群对乙肝表面抗原HBsAg的抗体免疫应答机制及其应用研究

乙肝病毒感染是我国乃至全球重大的健康问题之一。具有不同免疫史（乙肝疫苗接种者或乙肝病毒感染恢复者）的个体能产生乙肝表面抗体（anti-HBs），而慢性乙肝患者则由于不能产生乙肝表面抗体而使其体内存在大量的乙肝表面抗原（HBsAg）颗粒。近年来，探索利用单克隆抗体清除体内乙肝病毒从而“功能性治愈”慢性乙肝的临床策略成为研究热点。然而，众多已报道的乙肝表面抗体株或为鼠源、或丢失了抗体序列的天然性（如重链、轻链的非天然配对）、或缺乏较强的中和效力。因此，本项目计划招募具有不同免疫史的志愿者，系统性地研究人体乙肝表面抗体的免疫应答机制，并在单细胞水平探索抗体功能与其相应记忆性B细胞表达谱之间的关系。在此基础上，本项目将筛选“超级抗体应答者”，从中克隆具有极高中和效力的全天然人源抗体，并利用人肝小鼠模型来验证其体内保护效力及治疗作用，从而推动探索利用全天然人源单克隆中和抗体治疗慢性乙肝的临床策略。

Hepatitis B virus (HBV) infection remains a major global health problem. Both vaccinated and infected but recovered individuals develop anti-HBs antibodies, while the chronic HBV infected patients with a substantial amount of HBsAg particles in their blood fail to produce anti-HBs antibodies. Recently, to explore the possibility of “functional recovery” by using anti-HBs monoclonal antibodies is under investigation and discussion. However, most of the identified anti-HBs are either cloned from mouse, or lacks the natural pairing of heavy and light chains, or not very potent in their neutralizing effects. Here, in this proposed project, we will recruit volunteers with various immune histories (vaccinated or recovered) and systematically study their antibody immune response against HBsAg at the single-memory-B-cell level. We will also investigate the relationship between the properties of coded antibodies and the corresponding memory B cell transcriptome. Based on these fundamental characterizations, we will further identify “elite neutralizers” among donors and isolate the most potent neutralizing anti-HBs antibodies, which will be tested for their in vivo prophylaxis and treatment effect by using humanized liver mouse model. In summary, this project aims to study the anti-HBs antibody immune response from the donors with various immune histories, and also aims to promote the antibody treatment strategy by identifying natural human antibodies with very broad and potent neutralizing activities.