基于B细胞表位的独特微粒疫苗显示小鼠中乙型肝炎表面抗原

StephenW

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

    Tian-Ying Zhang1,2, Xue-Ran Guo1,2, Yang-Tao Wu1,2, Xiao-Zhen Kang1,2, Qing-Bing Zheng1,2, Ruo-Yao Qi1,2, Bin-Bing Chen1,2, Ying Lan1,2, Min Wei1,2, Shao-Juan Wang1,2, Hua-Long Xiong1,2, Jia-Li Cao1,2, Bao-Hui Zhang1,2, Xiao-Yang Qiao1,2, Xiao-Fen Huang1,2, Ying-Bin Wang1,2, Mu-Jin Fang1,2, Ya-Li Zhang1,2, Tong Cheng1,2, Yi-Xin Chen1,2, Qin-Jian Zhao1,2, Shao-Wei Li1,2, Sheng-Xiang Ge1,2, Pei-Jer Chen3, Jun Zhang1,2, Quan Yuan1,2, Ning-shao Xia1,2

Author affiliations

    State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health & School of Life Science, Xiamen University, Xiamen, China
    National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health & School of Life Science, Xiamen University, Xiamen, China
    Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan

    Correspondence to Professor Jun Zhang; [email protected], Dr Quan Yuan; [email protected] and Professor Ning-shao Xia; [email protected]

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.

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

http://dx.doi.org/10.1136/gutjnl-2018-317725

StephenW

基于B细胞表位的独特微粒疫苗显示小鼠中乙型肝炎表面抗原的有效抑制

    张天英1,2，郭雪然1,2，吴杨涛1,2，郑小兵1,2，郑庆兵1,2，刘若尧1,2，陈斌兵1,2 Lan1,2，Min Wei1,2，王少娟1,2，熊华龙1,2，曹佳丽1,2，张宝辉1,2，乔晓阳1,2，黄晓芬1,2 ，王迎斌1,2，方木瑾1,2，张亚丽1,2，佟成1,2，陈义新1,2，赵勤建1,2，李少伟1,2，盛 - 向戈1,2，陈佩杰3，张军1,2，全元1,2，夏宁少1,2

作者隶属关系

    厦门大学公共卫生学院生命科学学院分子疫苗学与分子诊断国家重点实验室，厦门
    厦门大学公共卫生学院生命科学学院传染病诊断与疫苗研究所，厦门
    台湾台北国立台湾大学医院肝炎研究中心

    与张军教授的通讯; [email protected]，泉源博士; [email protected]和Xia-shao Xia教授; [email protected]

抽象

目的本研究旨在开发一种基于独特B细胞表位的新型治疗性疫苗，并研究其在动物模型中对慢性乙型肝炎（CHB）的治疗潜力。

方法在HBV耐受小鼠中评估一系列肽和载体蛋白，以获得优化的治疗分子。系统研究了候选物的免疫原性，治疗效果和作用机制。

结果在该研究中评估的含HBsAg-aa119-125的肽中，HBsAg-aa113-135（SEQ13）表现出最显着的治疗效果。产生衍生自圆叶蝙蝠HBV核心抗原（RBHBcAg）的新型免疫增强病毒样颗粒载体（CR-T3）并用于展示SEQ13，形成候选分子CR-T3-SEQ13。在该颗粒抗原表面上展示的SEQ13的多个拷贝促进在小鼠，兔和食蟹猴中诱导有效的抗HBs抗体应答。来自免疫动物的血清和纯化的多克隆IgG在体外中和HBV感染并且在小鼠中介导有效的HBV /乙型肝炎病毒表面抗原（HBsAg）清除。基于CR-T3-SEQ13的疫苗接种诱导HBV转基因小鼠中HBsAg和HBV DNA的长期抑制，并在基于流体动力学的HBV携带者小鼠中完全根除病毒。对HBsAg的抑制作用与疫苗接种后的抗-HBs水平强烈相关，表明CR-T3-SEQ13疫苗接种疗法的主要机制是诱导介导HBV / HBsAg清除的SEQ13特异性抗体应答。

结论新型颗粒蛋白CR-T3-SEQ13通过诱导HBV耐受小鼠的幽门免疫应答有效抑制HBsAg。这种基于B细胞表位的治疗性疫苗可以提供抗人类慢性HBV感染的新型免疫治疗剂。

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http://dx.doi.org/10.1136/gutjnl-2018-317725

StephenW

https://gut.bmj.com/content/earl ... p;utm_term=04042019