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Gut. 2019 Mar 29. pii: gutjnl-2018-317725. doi: 10.1136/gutjnl-2018-317725. [Epub ahead of print]
A unique B cell epitope-based particulate vaccine shows effective suppression of hepatitis B surface antigen in mice.
Zhang TY#1,2, Guo XR#1,2, Wu YT#1,2, Kang XZ1,2, Zheng QB1,2, Qi RY1,2, Chen BB1,2, Lan Y1,2, Wei M1,2, Wang SJ1,2, Xiong HL1,2, Cao JL1,2, Zhang BH1,2, Qiao XY1,2, Huang XF1,2, Wang YB1,2, Fang MJ1,2, Zhang YL1,2, Cheng T1,2, Chen YX1,2, Zhao QJ1,2, Li SW1,2, Ge SX1,2, Chen PJ3, Zhang J1,2, Yuan Q1,2, Xia NS1,2.
Author information
1
State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health & School of Life Science, Xiamen University, Xiamen, China.
2
National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health & School of Life Science, Xiamen University, Xiamen, China.
3
Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan.
#
Contributed equally
Abstract
OBJECTIVE:
This 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.
METHODS:
A 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.
RESULTS:
Among 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.
CONCLUSIONS:
The 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.
© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
KEYWORDS:
drug development; hepatitis B; immunotherapy
PMID:
30926653
DOI:
10.1136/gutjnl-2018-317725 |
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