病毒样囊泡为基础的治疗性疫苗载体慢性乙型肝炎病毒感染

StephenW

Virus-Like Vesicle-Based Therapeutic Vaccine Vectors for Chronic Hepatitis B Virus Infection

    Tracy D. Reynolds†, Linda Buonocore, Nina F. Rose, John K. Rose and Michael D. Robek*

    Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA

    G. McFadden, Editor

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Author Affiliations
ABSTRACT

More than 500,000 people die each year from the liver diseases that result from chronic hepatitis B virus (HBV) infection. Therapeutic vaccines, which aim to elicit an immune response capable of controlling the virus, offer a potential new treatment strategy for chronic hepatitis B. Recently, an evolved, high-titer vaccine platform consisting of Semliki Forest virus RNA replicons that express the vesicular stomatitis virus glycoprotein (VSV G) has been described. This platform generates virus-like vesicles (VLVs) that contain VSV G but no other viral structural proteins. We report here that the evolved VLV vector engineered to additionally express the HBV middle surface envelope glycoprotein (MHBs) induces functional CD8 T cell responses in mice. These responses were greater in magnitude and broader in specificity than those obtained with other immunization strategies, including recombinant protein and DNA. Additionally, a single immunization with VLV-MHBs protected mice from HBV hydrodynamic challenge, and this protection correlated with the elicitation of a CD8 T cell recall response. In contrast to MHBs, a VLV expressing HBV core protein (HBcAg) neither induced a CD8 T cell response in mice nor protected against challenge. Finally, combining DNA and VLV-MHBs immunization led to induction of HBV-specific CD8 T cell responses in a transgenic mouse model of chronic HBV infection. The ability of VLV-MHBs to induce a multispecific T cell response capable of controlling HBV replication, and to generate immune responses in a tolerogenic model of chronic infection, indicates that VLV vaccine platforms may offer a unique strategy for HBV therapeutic vaccination.

IMPORTANCE HBV infection is associated with significant morbidity and mortality. Furthermore, treatments for chronic infection are suboptimal and rarely result in complete elimination of the virus. Therapeutic vaccines represent a unique approach to HBV treatment and have the potential to induce long-term control of infection. Recently, a virus-based vector system that combines the nonstructural proteins of Semliki Forest virus with the VSV glycoprotein has been described. In this study, we used this system to construct a novel HBV vaccine and demonstrated that the vaccine is capable of inducing virus-specific immune responses in mouse models of acute and chronic HBV replication. These findings highlight the potential of this new vaccine system and support the idea that highly immunogenic vaccines, such as viral vectors, may be useful in the treatment of chronic hepatitis B.

This paper is dedicated to the memory of the first author, Tracy D. Reynolds.
FOOTNOTES

        Received 8 May 2015.
        Accepted 29 July 2015.
        Accepted manuscript posted online 5 August 2015.
    Address correspondence to Michael D. Robek, [email protected].

    ↵* Present address: Michael D. Robek, Center for Immunology & Microbial Disease, Albany Medical College, Albany, New York, USA.

    ↵† Deceased.

StephenW

病毒样囊泡为基础的治疗性疫苗载体慢性乙型肝炎病毒感染

    特雷西D.雷诺兹†，琳达Buonocore，龚如心楼罗斯，约翰·K. Rose和迈克尔·Robek *

    病理科，耶鲁大学医学院，纽黑文，康涅狄格，美国

    G.麦克法登，编辑器

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作者机构
摘要

有超过50万人每年死于而导致的慢性乙型肝炎病毒（HBV）感染的肝脏疾病。治疗性疫苗，其目的是引起能够控制病毒的免疫反应，提供了潜在的新的治疗策略用于治疗慢性乙型肝炎近来，演进，高滴度的疫苗平台，包括塞姆利基森林病毒的RNA复制子表达的水泡性口炎病毒糖蛋白（VSV G）进行了说明。这个平台产生病毒样囊泡（VLVs）包含VSVģ但没有其它病毒结构蛋白。我们这里报告的演进VLV矢量工程化以附加地表现中间乙肝表面包膜糖蛋白（MHBs）诱导小鼠官能的CD8 T细胞应答。这些反应是在更大程度和更广的特异性高于其他免疫策略，包括重组蛋白和DNA获得。此外，随着VLV-MHBs单次免疫保护小鼠从HBV的流体动力挑战，并且这种保护相关与CD8 T细胞的记忆反应的诱导。在对比MHBs，一个VLV表达HBV核心蛋白（核心抗原）既不在小鼠中诱导一个CD8 + T细胞应答也没有保护，以防止挑战。最后，结合的DNA和VLV-MHBs免疫导致诱导乙型肝炎病毒特异性CD8 T细胞应答在慢性HBV感染的转基因小鼠模型。 VLV-MHBs的诱导多特异性T细胞应答能够控制HBV复制，并产生慢性感染的致耐受性模型的免疫反应的能力，表明VLV疫苗平台可能提供乙肝治疗性疫苗接种的唯一策略。

重要性HBV感染与显著发病率和死亡率相关联。此外，对于慢性感染的治疗是不理想的，很少导致完全消除病毒。治疗性疫苗代表一种独特的方法来治疗的HBV和具有诱导长期控制感染的潜力。近来，基于病毒的载体系统，结合Semliki森林病毒与VSV的糖蛋白的非结构蛋白已经描述。在这项研究中，我们使用这个系统构建了一种新的乙肝疫苗并证明了该疫苗能够诱导在急性和慢性HBV复制的小鼠模型病毒特异性免疫应答的。这些发现强调这种新疫苗系统的潜能和支持这一想法，高度免疫原性的疫苗，如病毒载体，可以是在慢性乙型肝炎的治疗有用

本文是专门为第一作者，特雷西D.雷诺兹的记忆。
脚注

        收到的2015年8月。
        接受2015年29月。
        接受稿件在线5发布2015年八月。
    通讯地址迈克尔·Robek，[email protected]。

    ↵*现住址：迈克尔·Robek，中心免疫学及微生物病害，奥尔巴尼医学院，奥尔巴尼，纽约，美国。

    ↵†死者。

MP4

Deceased.