一种独特的基于B细胞抗原决定簇的颗粒疫苗可有效抑制小鼠

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

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Significance of this study
What is already known on this subject?

    Achievement of hepatitis B virus surface antigen (HBsAg) loss is an ideal endpoint of chronic hepatitis B (CHB) treatment, and it is rarely achieved by current approved anti-HBV drugs.

    High load of HBsAg directly inhibit both adaptive and innate immune functions and ultimately leads to specific tolerance that prevents the host from eradicating HBV infection. A long-term suppression of HBsAg hopefully allows for restoration of anti-HBs B cell response and HBV specific T cell function.

    Most HBV therapeutic vaccines based on the native HBsAg and HBcAg could induce specific T cells in HBV carrier mice, even in patients with CHB, but there was no significant effective antibody response that mediates viral clearance, thus exhibited limited inhibitory effect on HBsAg levels.

    The antibodies recognise the sA epitope (HBsAg-aa119-125) and exhibit more remarkable and prolonged HBsAg suppression effects than antibodies binding to other epitopes as we described previously.

Significance of this study
What are the new findings?

    Among the HBsAg-aa119-125-containing peptides evaluated in this study, HBsAg-aa113-135 (SEQ13) exhibited the most striking therapeutic effects. A novel immuno-enhanced virus-like particle carrier (CR-T3) derived from the roundleaf bat HBV core antigen (RBHBcAg) was created and used to display SEQ13, forming the novel particulate protein CR-T3-SEQ13.

    Multiple copies of SEQ13 displayed on the surface of this particulate antigen promote the induction of a potent antibody response in mice, rabbits and cynomolgus monkeys, and dominant antibodies recognise HBsAg-aa119-125, which exhibit broad spectrum of activity to mediate HBsAg clearance in vivo and neutralise HBV infection in vitro.

    CR-T3-SEQ13-based vaccination showed a long-term suppression of HBsAg and HBV DNA in HBV transgenic mice and eradicated the virus completely in hydrodynamic-based HBV carrier mice by induction of a SEQ13-specific antibody response that mediated HBV/HBsAg clearance.

How might it impact on clinical practice in the foreseeable future?

    CR-T3-SEQ13 is a superior candidate based on a unique B cell eiptope for developing therapeutic vaccine against HBV, which will be tested in the clinic alone or in combination with current available anti-HBV drugs to treat patients with CHB, and aims to increase the HBsAg loss rate.

    If successful, CR-T3-SEQ13-based immunotherapy will provide a novel anti-HBV strategy to achieve long-term inhibition of the HBsAg levels and improve the clinical management of CHB.

StephenW

一种独特的基于B细胞抗原决定簇的颗粒疫苗可有效抑制小鼠的乙肝表面抗原

    张天英1,2，郭雪然1,2，吴杨涛1,2，康晓珍1,2，郑庆兵1,2，齐若瑶1,2，陈斌兵1,2，颖兰1,2，闵伟1,2，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 ，王英斌1,2，方木金1,2，张亚丽1,2，童成1,2，陈以新1,2，赵钦建1,2，李少伟1,2，盛胜，项格1,2，陈佩杰3，张军1,2，泉源1,2，夏宁韶1,2

作者单位

    厦门大学公共卫生学院和生命科学学院分子疫苗学和分子诊断国家重点实验室
    厦门大学公共卫生学院和生命科学学院，国家传染病诊断和疫苗开发研究所，厦门
    国立台湾大学附属医院肝炎研究中心，台湾台北

    对应张军教授； [email protected]，Quan Yuan博士； [email protected]和夏宁韶教授； [email protected]

抽象

目的这项研究旨在开发一种基于独特的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。

方法在耐HBV的小鼠中评估一系列肽和载体蛋白，以获得优化的治疗分子。系统地研究了该候选人的免疫原性，疗效和机制。

结果在这项研究中评估的含HBsAg-aa119-125的肽中，HBsAg-aa113-135（SEQ13）表现出最显着的治疗效果。创建了一种新的源自圆叶蝙蝠HBV核心抗原（RBHBcAg）的免疫增强病毒样颗粒载体（CR-T3），并用于显示SEQ13，从而形成候选分子CR-T3-SEQ13。在该微粒抗原的表面上展示的SEQ13的多个拷贝促进了在小鼠，兔子和食蟹猴中诱导有效的抗HBs抗体反应。来自免疫动物的血清和纯化的多克隆IgG在体外中和了HBV感染，并在小鼠中介导了有效的HBV /乙型肝炎病毒表面抗原（HBsAg）清除。基于CR-T3-SEQ13的疫苗接种可长期抑制HBV转基因小鼠中的HBsAg和HBV DNA，并彻底根除基于水动力的HBV携带者小鼠中的病毒。疫苗接种后对HBsAg的抑制作用与抗HBs水平密切相关，这表明CR-T3-SEQ13疫苗接种治疗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可通过诱导HBV耐受小鼠的体液免疫反应来有效抑制HBsAg。这种基于B细胞抗原决定簇的治疗性疫苗可以为人类的慢性HBV感染提供一种新型的免疫治疗剂。
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这项研究的意义
在这个问题上已经知道了什么？

    乙型肝炎病毒表面抗原（HBsAg）丢失的实现是慢性乙型肝炎（CHB）治疗的理想终点，而当前批准的抗HBV药物很少实现这一目标。

    高负荷的HBsAg直接抑制适应性免疫和先天免疫功能，并最终导致特定的耐受性，阻止宿主根除HBV感染。长期抑制HBsAg有望恢复抗HBs B细胞反应和HBV特异性T细胞功能。

    大多数基于天然HBsAg和HBcAg的HBV治疗疫苗即使在患有CHB的患者中也能在HBV携带者小鼠中诱导特异性T细胞，但没有显着的有效抗体反应介导病毒清除，因此对HBsAg水平的抑制作用有限。

    抗体识别sA表位（HBsAg-aa119-125），并比我们先前所述的结合其他表位的抗体表现出更显着和更长的HBsAg抑制作用。

这项研究的意义
有哪些新发现？
在这项研究中评估的含HBsAg-aa119-125的肽中，HBsAg-aa113-135（SEQ13）表现出最显着的治疗效果。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，形成了新型颗粒蛋白CR-T3-SEQ13。

    在该颗粒抗原的表面上显示的SEQ13的多个副本可促进在小鼠，兔子和食蟹猴中诱导有效的抗体反应，并且优势抗体识别HBsAg-aa119-125，后者具有介导体内介导HBsAg清除的广谱活性并在体外中和HBV感染。

    基于CR-T3-SEQ13的疫苗接种显示了对HBV转基因小鼠中HBsAg和HBV DNA的长期抑制，并通过诱导介导HBV / HBsAg清除的SEQ13特异性抗体应答，在基于水动力的HBV携带者小鼠中彻底根除了病毒。

在可预见的将来会对临床实践产生怎样的影响？

    CR-T3-SEQ13是基于独特的B细胞表位开发抗HBV治疗疫苗的优秀候选药物，将单独在临床中进行测试或与目前可用的抗HBV药物联合治疗CHB患者，并旨在增加HBsAg丢失率。

    如果成功，基于CR-T3-SEQ13的免疫疗法将提供一种新颖的抗HBV策略，以实现对HBsAg水平的长期抑制并改善CHB的临床管理。

StephenW

https://gut.bmj.com/content/69/2 ... p;utm_term=07012020