Engineered virus-hunter vaccine overcomes HBV immune tolerance

作者：Xiaoqing Chen, Xue Liu, Tao Xu, Yalin Wang, Peng Wang, Han Liu, Yichao Jiang, Xiaojing Qin, Liang Zhang, Yueting Xiong, Jian-cheng Ding, Yuanzhi Chen, Fentian Chen, Wenjing Ning, Hongye Zeng, Shiting Yang, Xu Lin, Tianying Zhang, Quan Yuan, Chao Liu, Wenxin Luo, Ningshao Xia · 发表于：Gut · 年份：2025 · DOI：10.1136/gutjnl-2025-335806 · 被引用次数：3 · 研究领域：Hepatitis B Virus Studies、Bacteriophages and microbial interactions、Viral Infections and Outbreaks Research

Background Globally, an estimated 296 million individuals live with chronic hepatitis B virus (HBV) infection, carrying substantial risks of liver fibrosis, cirrhosis and hepatocellular carcinoma. Fewer than 20% of patients receiving nucleos(t)ide analogues or interferons achieve a functional cure, underscoring the urgent need for novel therapeutic strategies to improve clinical outcomes in patients with chronic HBV infection. Objective The aim of this study was to develop a ‘virus-hunter vaccine’ that hijacks HBV antigens as endogenous immunogens, reprogramming dendritic cells (DCs) to prime anti-HBV immunity, ultimately achieving a durable functional cure beyond current therapeutic limitations. Design We engineered the SHARP (Specific HBV Antigen-capturing and Rendering Promotor) vaccine platform, comprising a bispecific antibody targeting hepatitis B surface antigen (HBsAg) and DEC-205, conjugated with toll-like receptor 7/8 agonists. Therapeutic efficacy was assessed in chronic HBV carrier mice, with comprehensive investigation of immunological mechanisms. Results Both SHARP variants demonstrated enhanced antigen phagocytosis, maturation and antigen presentation of DCs. Notably, SHARP-D265A (DA) emerged as the lead candidate due to its optimised Fc silencing, showing superior therapeutic efficacy with a lower anti-drug antibody incidence. SHARP treatment reversed the tolerogenic microenvironment through coordinated activation of HBV-specific CD4 + and CD8 + T cells and es...