Enhanced hepatitis B virus-specific immunity by combined neutralizing antibody therapy and DNA vaccination in a murine model of chronic hepatitis B infection

Background & Aims: Successful treatment of chronic HBV infection remains a great challenge due to the difficulty in inducing efficient immune responses. Here, we investigated the therapeutic potential of DNA vaccination combined with a potent HBV broadly neutralizing antibody (bNAb) targeting the small surface viral antigen. Approach & Results: C57BL/6 mice were transduced with adeno-associated virus (AAV)-HBV and were treated twice a week with HBV bNAb for 5 weeks. A DNA-based vaccine encoding the HBV core, envelope, and polymerase proteins was administered once to mice 3 weeks after initiating of antibody therapy. The antiviral effects and antigen-specific immune responses were evaluated before and for 8 weeks after therapeutic vaccination. Vaccine administration with or without antibody treatment induced the development of functional HBV-specific CD8+ T cells and envelope-specific resident memory T cells in the liver. The combination of antibody treatment and DNA vaccination enhanced the recruitment of B and CD8+ T lymphocytes into the liver of HBV-carrier mice two weeks after vaccination. However, although still detectable 2 months after vaccination, HBV-specific CD8+ T cells showed an exhausted phenotype, suggesting that they are dysfunctional. In contrast, a more effective control of antigenemia was observed following combination therapy, which was associated with the presence of HBs-specific memory B cells. Conclusions: Although the combination therapy did not result in a functional cure, our findings indicate it produced additive effects on the development of HBV-specific T cells in the liver immediately following treatment, offering a better insight into the mechanisms underlying hepatic tolerance.