Immune Profiles Elicited by Different HBV Vaccine Modalities and Their Associations with Serological and Intrahepatic Viral Outcomes

Therapeutic vaccination for chronic hepatitis B aims to restore HBV-specific T-cell immunity and contribute to a functional cure. We systematically compared the immune profiles and antiviral efficacy of four vaccine modalities: recombinant HBsAg (rHBsAg), antigen–antibody immune complex (IC), a DNA vaccine encoding HBsAg (DNA-HBsAg), and an HBsAg-Fc fusion DNA vaccine (DNA-HBsAg-Fc). In naïve mice, the rHBsAg vaccine predominantly induced anti-HBs IgG responses, whereas the IC vaccine elicited strong anti-HBs IgG and detectable CD4⁺ T-cell responses. In contrast, DNA vaccines preferentially induced HBsAg-specific CD8⁺ T-cell immunity, which was further enhanced by fusion to the Fc fragment of human IgG1. In the pre-immunization/AAV-HBV model, high anti-HBs titers in rHBsAg and IC groups were associated with rapid clearance of circulating HBsAg but not with comparable reductions in HBcAg⁺ hepatocytes, whereas stronger HBsAg-specific CD8⁺ T-cell responses in the DNA vaccine groups were associated with greater reductions in HBcAg⁺ hepatocytes. However, in the therapeutic AAV-HBV model, all vaccine monotherapies showed limited and non-sustained antiviral efficacy, with only transient reductions in serum HBsAg and limited reductions in HBcAg⁺ hepatocytes. These findings highlight the distinct immune profiles of different vaccine platforms and an association between stronger HBsAg-specific CD8⁺ T-cell responses and reduced intrahepatic HBcAg expression, while underscoring the limited efficacy of vaccine monotherapy in the AAV-HBV model.