Clearing Persistent Extracellular Antigen of Hepatitis B Virus: An Immunomodulatory Strategy To Reverse Tolerance for an Effective Therapeutic Vaccination

Development of therapeutic vaccines/strategies to control chronic hepatitis B virus (HBV) infection (CHB) has been challenging due to HBV-induced tolerance. In this study, we explored strategies for breaking tolerance and restoring the immune response to the HBV surface antigen in tolerant mice. We demonstrated that immune tolerance status is attributed to the level and duration of circulating HBsAg in HBV carrier models. Removal of circulating HBsAg by a monoclonal anti-HBsAg antibody in tolerant mice could gradually reduce tolerance and reestablish B cell and CD4+ T cell responses to subsequent Engerix-B vaccination, producing protective IgG. Furthermore, HBsAg-specific CD8+ T cells induced by the addition of a TLR agonist, resulted in clearance of HBV in both serum and liver. Thus, generation of protective immunity can be achieved by clearing extracellular viral antigen with neutralizing antibodies followed by vaccination