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
  • 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.
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