乙肝表面抗原（HBsAg）难以清除是慢乙肝抗病毒治疗面临的重大挑战，目前尚无治疗手段直接靶向HBsAg清除。我们初步结果发现B细胞缺陷小鼠血清HBsAg清除延迟，表明B细胞在HBsAg清除过程中发挥重要作用，但体外研究提示HBsAg的浓度和表位对B细胞免疫应答具有重要影响，由此我们推断HBsAg与B细胞之间的交互作用影响HBsAg清除。本项目拟通过慢性HBV感染横向人群和抗病毒治疗纵向队列、体外实验以及HBV小鼠模型，从HBsAg对B细胞的免疫调节作用、HBsAg特异性B细胞表位分析、HBsAg特异性B细胞受体基因序列差异以及HBsAg表位多肽疫苗和表位特异性抗体的抗病毒效应等方面进行研究，目的在于阐明B细胞在HBsAg清除中的作用机制以及筛选出与HBsAg清除直接关联的HBsAg特异性B细胞表位和具有治疗潜能的单克隆抗体，这对开发直接靶向HBsAg清除的慢乙肝免疫治疗新策略具有重要意义。

The difficulty of hepatitis B surface antigen (HBsAg) clearance is the major challenge for antiviral treatment in chronic hepatitis B (CHB) patients with currently available drugs, till now there is no therapeutic directly target HBsAg clearance. Our preliminary results showed the delayed clearance of serum HBsAg in HBV mouse model established by B cell deficiency mice, indicating the critical role of B cells in the process of HBsAg clearance. However, in vitro studies suggested that the concentration and epitopes of HBsAg have significant effects on B cell immune response, thus we speculated that the interaction between HBsAg and B cells may influence the clearance of HBsAg. Herein, with the help of cross-sectional cohort with chronic HBV infection and longitudinal cohort with antiviral treatment, and in combination with in vitro experiments and mouse model with HBV expression, we plan to explore this issue in the following aspects: the immune regulatory effect of HBsAg on B cell function, the analyses of HBsAg specific B cell epitopes, the differences among gene sequences of HBsAg specific B cell receptors, and the anti-HBV efficacy of HBsAg epitope-specific monoclonal antibody and HBsAg epitope peptides. This project aims to illuminate the functional mechanism of B cell in the process of HBsAg clearance, and discover the B cell epitopes that directly associated with HBsAg clearance as well as the monoclonal antibody with therapeutic potential against HBsAg. This research will help to provide significant implications for the development of novel immunotherapeutic strategies that target HBsAg clearance in the clinical management of chronic HBV infection.