A unique B cell epitope-based particulate vaccine shows effective suppression of hepatitis B surface antigen in mice

• Published in: Gut Vol. 69; no. 2; pp. 343 - 354
• Main Authors: Zhang, Tian-Ying, Guo, Xue-Ran, Wu, Yang-Tao, Kang, Xiao-Zhen, Zheng, Qing-Bing, Qi, Ruo-Yao, Chen, Bin-Bing, Lan, Ying, Wei, Min, Wang, Shao-Juan, Xiong, Hua-Long, Cao, Jia-Li, Zhang, Bao-Hui, Qiao, Xiao-Yang, Huang, Xiao-Fen, Wang, Ying-Bin, Fang, Mu-Jin, Zhang, Ya-Li, Cheng, Tong, Chen, Yi-Xin, Zhao, Qin-Jian, Li, Shao-Wei, Ge, Sheng-Xiang, Chen, Pei-Jer, Zhang, Jun, Yuan, Quan, Xia, Ning-shao
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group LTD 01.02.2020; BMJ Publishing Group
• Series: Original research
• Subjects: Adjuvants, Immunologic; Animal models; Animals; Antibody response; Antigens; Antiviral Agents - therapeutic use; Chronic infection; Combined Modality Therapy; Core protein; DNA, Viral - blood; Dose-Response Relationship, Immunologic; Drugs; Epitopes; Epitopes, B-Lymphocyte - immunology; Experiments; Female; Hepatitis; Hepatitis B Antibodies - biosynthesis; Hepatitis B surface antigen; Hepatitis B Surface Antigens - blood; Hepatitis B Vaccines - immunology; Hepatitis B Vaccines - therapeutic use; Hepatitis B virus - genetics; Hepatitis B, Chronic - immunology; Hepatitis B, Chronic - therapy; Hepatitis B, Chronic - virology; Hepatology; Immune clearance; Immunity, Humoral - immunology; Immunogenicity; Immunoglobulin G; Immunoglobulins; Immunotherapy; Immunotherapy - methods; Infections; Laboratory animals; Lymphocytes; Macaca fascicularis; Male; Mice, Inbred BALB C; Mice, Transgenic; Rabbits; Transgenic mice; Vaccination; Vaccines; Viral infections; Virus-like particles; Viruses; drug development; hepatitis B; immunotherapy
• ISSN: 0017-5749; 1468-3288
• DOI: 10.1136/gutjnl-2018-317725

ObjectiveThis study aimed to develop a novel therapeutic vaccine based on a unique B cell epitope and investigate its therapeutic potential against chronic hepatitis B (CHB) in animal models.MethodsA series of peptides and carrier proteins were evaluated in HBV-tolerant mice to obtain an optimised therapeutic molecule. The immunogenicity, therapeutic efficacy and mechanism of the candidate were investigated systematically.ResultsAmong the HBsAg-aa119-125-containing peptides evaluated in this study, HBsAg-aa113-135 (SEQ13) exhibited the most striking therapeutic effects. A novel immunoenhanced virus-like particle carrier (CR-T3) derived from the roundleaf bat HBV core antigen (RBHBcAg) was created and used to display SEQ13, forming candidate molecule CR-T3-SEQ13. Multiple copies of SEQ13 displayed on the surface of this particulate antigen promote the induction of a potent anti-HBs antibody response in mice, rabbits and cynomolgus monkeys. Sera and purified polyclonal IgG from the immunised animals neutralised HBV infection in vitro and mediated efficient HBV/hepatitis B virus surface antigen (HBsAg) clearance in the mice. CR-T3-SEQ13-based vaccination induced long-term suppression of HBsAg and HBV DNA in HBV transgenic mice and eradicated the virus completely in hydrodynamic-based HBV carrier mice. The suppressive effects on HBsAg were strongly correlated with the anti-HBs level after vaccination, suggesting that the main mechanism of CR-T3-SEQ13 vaccination therapy was the induction of a SEQ13-specific antibody response that mediated HBV/HBsAg clearance.ConclusionsThe novel particulate protein CR-T3-SEQ13 suppressed HBsAg effectively through induction of a humoural immune response in HBV-tolerant mice. This B cell epitope-based therapeutic vaccine may provide a novel immunotherapeutic agent against chronic HBV infection in humans.