2. Academic Validation
  3. Engineered virus-hunter vaccine overcomes HBV immune tolerance

Engineered virus-hunter vaccine overcomes HBV immune tolerance

  • Gut. 2025 Nov 12:gutjnl-2025-335806. doi: 10.1136/gutjnl-2025-335806.
Xiaoqing Chen 1 2,  Xue Liu 3 2,  Tao Xu 1 2,  Yalin Wang 1 2,  Peng Wang 1 2,  Han Liu 1 2,  Yichao Jiang 1 2,  Xiaojing Qin 1 2,  Liang Zhang 1 2,  Yueting Xiong 1,  Jiancheng Ding 1,  Yuanzhi Chen 1 2,  Fentian Chen 1 2,  Wenjing Ning 1 2,  Hongye Zeng 1 2,  Shiting Yang 1 2,  Lin Xu 1 2,  Tianying Zhang 1 2,  Quan Yuan 1 2,  Chao Liu 4 5,  Wenxin Luo 3 2,  Ningshao Xia 3 2
Affiliations

Affiliations

  • 1 State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen, Fujian, China.
  • 2 National Institute of Diagnostics and Vaccine Development in Infectious Diseases, National Innovation Platform for Industry-Education Integration in Vaccine Research, the Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical Sciences, Xiamen University, Xiamen, Fujian, China.
  • 3 State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen, Fujian, China [email protected] [email protected] [email protected] [email protected].
  • 4 State Key Laboratory of Vaccines for Infectious Diseases, Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian, China [email protected] [email protected] [email protected] [email protected].
  • 5 Shenzhen Research Institute of Xiamen University, Shenzhen, Guangdong, China.
PMID: 41198172 DOI: 10.1136/gutjnl-2025-335806
Abstract

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 established durable viral control: HBsAg was below the limit of detection, accompanied by the appearance of anti-HBsAg, which was maintained for more than 161 days with established immune memory against rechallenge.

Conclusion: This innovative HBV vaccine strategy actively captures viruses, overcoming the tolerogenic immune microenvironment of chronic HBV Infection, offering a novel strategy for the treatment of chronic HBV Infection and Other immune-tolerant diseases.

Keywords

ANTIBODY TARGETED THERAPY; ANTIVIRAL THERAPY; CHRONIC HEPATITIS; DRUG DEVELOPMENT; IMMUNE RESPONSE.

Figures
Products