Clearing Persistent Extracellular Antigen of Hepatitis B Virus: An Immunomodulatory Strategy To Reverse Tolerance for an Effective Therapeutic Vaccination
Danming Zhu*,1, Longchao Liu*,†,1, Dan Yang*, Sherry Fu‡, Yingjie Bian*,†, Zhichen Sun*,†, Junming He*, Lishan Su§, Liguo Zhang*, Hua Peng* and Yang-Xin Fu*,‡
+ Author Affiliations
*Institute of Biophysics–University of Texas Group for Immunotherapy, Chinese Academy of Sciences Key Laboratory for Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Chaoyang District, Beijing 100101, China;
†University of Chinese Academy of Sciences, Beijing 100049, China;
‡Department of Pathology and Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75225; and
§Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599
Address correspondence and reprint requests to Dr. Hua Peng and Dr. Yang-Xin Fu, Institute of Biophysics–University of Texas Group for Immunotherapy, Key Laboratory for Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Room 1507, Chaoyang District, Beijing 100101, China. E-mail addresses: ***@**** (H.P.) and Yang-Xin.***@**** (Y.-X.F.)
↵1 D.Z. and L.L. contributed equally to this work.
Development of therapeutic vaccines/strategies to control chronic hepatitis B virus (HBV) infection has been challenging because of HBV-induced tolerance. In this study, we explored strategies for breaking tolerance and restoring the immune response to the HBV surface Ag 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 Ab 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 Ag with neutralizing Abs followed by vaccination.