Abstact

Antibodies targeting the hepatitis B virus (HBV) surface antigens (HBsAg) are essential for the prevention and control of HBV infection, yet their molecular and functional properties remain incompletely understood. Here, we characterize HBV seroconverter-derived human memory B cell monoclonal antibodies targeting preS1, preS2, and small (S) HBsAg regions. We find that broadly reactive anti-preS2 antibodies neutralize HBV and exert Fc-dependent effector functions that significantly contribute to their in vivo antiviral activity in HBV-carrier mice. Mapping and structural analysis reveal that they target an immunodominant epitope at the N terminus of preS2. Combining anti-preS2 and anti-S broadly neutralizing antibodies (bNAbs) isolated from the same donor profoundly and durably reduces antigenemia and viremia in HBV-carrier mice. These findings underscore the antiviral potential of anti-preS2 antibodies, particularly when combined with potent anti-S bNAbs, emphasizing their relevance for enhancing HBV vaccine efficacy and advancing immunotherapy development.