抑制乙型肝炎和丁型肝炎病毒感染的新型初免免疫疗法

StephenW

抑制乙型肝炎和丁型肝炎病毒感染的新型初免免疫疗法
Rani Burm 1 , Panagiota Maravelia 2 , Gustaf Ahlen 2 , Sandra Ciesek 3 4 5 , Noelia Caro Perez 2 , Anna Pasetto 2 , Stephan Urban 6 , Freya Van Houtte 1 , Lieven Verhoye 1 , Heiner Wedemeyer 7 , Magnus Johansson 8 , Lars Frelin 2、马蒂·塞尔伯格 9、菲利普·穆勒曼 10
隶属关系
隶属关系

    1
    比利时根特大学医学与健康科学学院诊断科学系肝脏传染病实验室 (LLID)。
    2
    瑞典斯德哥尔摩卡罗林斯卡学院检验医学系临床微生物学系。
    3
    医学病毒学研究所，大学医院，歌德大学，法兰克福，德国。
    4
    弗劳恩霍夫转化医学和药理学研究所 ITMP，法兰克福，德国。
    5
    德国感染研究中心，DZIF，外部合作伙伴网站，德国美因河畔法兰克福。
    6
    德国海德堡海德堡大学医院传染病、分子病毒学系。
    7
    德国汉诺威汉诺威医学院胃肠病学、肝病学和内分泌学系。
    8
    瑞典厄勒布鲁厄勒布鲁大学医学与健康学院医学科学学院炎症反应和感染易感性中心 (iRiSC)。
    9
    瑞典斯德哥尔摩卡罗林斯卡医学院检验医学系临床微生物学系 [email protected] [email protected]。
    10
    比利时根特根特大学医学与健康科学学院诊断科学系肝脏传染病实验室 (LLID) [email protected] [email protected]。

    PMID：35977815 DOI：10.1136/gutjnl-2022-327216

抽象的

目的：慢性HBV/HDV感染是肝癌的主要原因。目前的治疗很少能消除 HBV 和 HDV。我们之前开发的 preS1-HDAg 免疫疗法可以在体内诱导针对 HBV 的中和抗体并提高 HBV/HDV 特异性 T 细胞。在这里，我们进一步研究异源初免增强策略是否可以规避 T 细胞耐受性并在体内排除 HDV 重复感染。

设计：在小鼠和兔子中评估了 DNA 启动蛋白增强策略的免疫原性。在免疫活性乙型肝炎表面抗原 (HBsAg) 转基因小鼠中评估了其规避 T 细胞耐受性的能力。在体外和过继转移后的免疫缺陷人肝嵌合小鼠中评估了 HBV 和 HDV 的中和作用。

结果：prime-boost 策略诱导出强大的 HBV/HDV 特异性 T 细胞和 preS1 抗体，可在体外和体内有效预防 HBV 和 HDV（共）感染。在代表慢性 HBsAg 携带者状态的小鼠模型中，主动免疫引发高水平的前 S1 抗体和 HDAg 特异性 T 细胞。此外，疫苗诱导抗体的转移完全保护了HBV感染的人肝嵌合小鼠免受HDV重复感染。

结论：本文描述的 preS1-HDAg 免疫疗法被证明具有免疫原性，并且疫苗诱导的抗体在体外和体内都非常有效地预防 HBV 和 HDV（超级）感染。我们的疫苗可以补充当前和未来用于控制慢性 HBV 和 HDV 感染的疗法。

关键词：抗病毒治疗；慢性病毒性肝炎；乙型肝炎；丁型肝炎；免疫疗法。

© Author(s) (或其雇主) 2022。不得商业再使用。请参阅权利和许可。由英国医学杂志出版

StephenW

Novel prime-boost immune-based therapy inhibiting both hepatitis B and D virus infections
Rani Burm  1 , Panagiota Maravelia  2 , Gustaf Ahlen  2 , Sandra Ciesek  3   4   5 , Noelia Caro Perez  2 , Anna Pasetto  2 , Stephan Urban  6 , Freya Van Houtte  1 , Lieven Verhoye  1 , Heiner Wedemeyer  7 , Magnus Johansson  8 , Lars Frelin  2 , Matti Sällberg  9 , Philip Meuleman  10
Affiliations
Affiliations

    1
    Laboratory of Liver Infectious Diseases (LLID), Department of Diagnostic Sciences, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium.
    2
    Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
    3
    Institute for Medical Virology, University Hospital, Goethe University, Frankfurt am Main, Germany.
    4
    Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Frankfurt am Main, Germany.
    5
    German Center for Infection Research, DZIF, External partner site, Frankfurt am Main, Germany.
    6
    Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, Heidelberg, Germany.
    7
    Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
    8
    School of Medical Sciences, Inflammatory Response and Infection Susceptibility Centre (iRiSC), Faculty of Medicine and Health, Örebro University, Orebro, Sweden.
    9
    Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden [email protected] [email protected].
    10
    Laboratory of Liver Infectious Diseases (LLID), Department of Diagnostic Sciences, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium [email protected] [email protected].

    PMID: 35977815 DOI: 10.1136/gutjnl-2022-327216

Abstract

Objective: Chronic HBV/HDV infections are a major cause of liver cancer. Current treatments can only rarely eliminate HBV and HDV. Our previously developed preS1-HDAg immunotherapy could induce neutralising antibodies to HBV in vivo and raise HBV/HDV-specific T-cells. Here, we further investigate if a heterologous prime-boost strategy can circumvent T-cell tolerance and preclude HDV superinfection in vivo.

Design: A DNA prime-protein boost strategy was evaluated for immunogenicity in mice and rabbits. Its ability to circumvent T-cell tolerance was assessed in immunocompetent hepatitis B surface antigen (HBsAg)-transgenic mice. Neutralisation of HBV and HDV was evaluated both in vitro and in immunodeficient human-liver chimeric mice upon adoptive transfer.

Results: The prime-boost strategy elicits robust HBV/HDV-specific T-cells and preS1-antibodies that can effectively prevent HBV and HDV (co-)infection in vitro and in vivo. In a mouse model representing the chronic HBsAg carrier state, active immunisation primes high levels of preS1-antibodies and HDAg-specific T-cells. Moreover, transfer of vaccine-induced antibodies completely protects HBV-infected human-liver chimeric mice from HDV superinfection.

Conclusion: The herein described preS1-HDAg immunotherapy is shown to be immunogenic and vaccine-induced antibodies are highly effective at preventing HBV and HDV (super)infection both in vitro and in vivo. Our vaccine can complement current and future therapies for the control of chronic HBV and HDV infection.

Keywords: antiviral therapy; chronic viral hepatitis; hepatitis B; hepatitis D; immunotherapy.

© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ