Engineered virus-hunter vaccine overcomes HBV immune tolerance

Engineered Virus-Hunter Vaccine Overcomes HBV Immune Tolerance

Background

Globally, about 296 million people live with chronic hepatitis B virus (HBV) infection, facing significant risks of liver fibrosis, cirrhosis, and hepatocellular carcinoma.

Objective

This study aimed to develop a "virus-hunter vaccine" that uses HBV antigens as endogenous immunogens to reprogram dendritic cells (DCs), priming anti-HBV immune responses for a durable functional cure beyond current treatments.

Design

The SHARP (Specific HBV Antigen-capturing and Rendering Promotor) vaccine platform was engineered, consisting of a bispecific antibody targeting hepatitis B surface antigen (HBsAg) and DEC-205, conjugated with toll-like receptor 7/8 agonists. Therapeutic impact was tested in chronic HBV carrier mice, with detailed immunological analysis.

Results

Both SHARP variants enhanced antigen phagocytosis, DC maturation, and antigen presentation.
SHARP-D265A (DA) was the lead candidate due to optimized Fc silencing, showing better therapeutic effects and fewer anti-drug antibodies.
SHARP therapy countered the tolerogenic environment by activating HBV-specific CD4+ and CD8+ T cells.
Durable viral control was achieved: HBsAg levels dropped below detection limits, anti-HBsAg antibodies appeared and persisted for over 161 days, accompanied by immune memory protecting against rechallenge.

"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."

Author’s Summary: The SHARP vaccine effectively reprograms immune cells to overcome HBV tolerance, offering a promising path toward lasting viral control and immune protection in chronic hepatitis B infection.

Gut — 2025-11-06