一种高度减毒的水泡性口腔炎病毒疫苗平台控制乙型肝炎小

StephenW

A Highly Attenuated Vesicular Stomatitis Virus-Based Vaccine Platform Controls Hepatitis B Virus Replication in Mouse Models of Hepatitis B
Safiehkhatoon Moshkani, Carolina Chiale, Sabine M. Lang, John K. Rose, Michael D. Robek
J.-H. James Ou, Editor
DOI: 10.1128/JVI.01586-18

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ABSTRACT

Therapeutic vaccines may be an important component of a treatment regimen for curing chronic hepatitis B virus (HBV) infection. We previously demonstrated that recombinant wild-type vesicular stomatitis virus (VSV) expressing the HBV middle surface glycoprotein (MHBs) elicits functional immune responses in mouse models of HBV replication. However, VSV has some undesirable pathogenic properties, and the use of this platform in humans requires further viral attenuation. We therefore generated a highly attenuated VSV that expresses MHBs and contains two attenuating mutations. This vector was evaluated for immunogenicity, pathogenesis, and anti-HBV function in mice. Compared to wild-type VSV, the highly attenuated virus displayed markedly reduced pathogenesis but induced similar MHBs-specific CD8+ T cell and antibody responses. The CD8+ T cell responses elicited by this vector in naive mice prevented HBV replication in animals that were later challenged by hydrodynamic injection or transduction with adeno-associated virus encoding the HBV genome (AAV-HBV). In mice in which persistent HBV replication was first established by AAV-HBV transduction, subsequent immunization with the attenuated VSV induced MHBs-specific CD8+ T cell responses that corresponded with reductions in serum and liver HBV antigens and nucleic acids. HBV control was associated with an increase in the frequency of intrahepatic HBV-specific CD8+ T cells and a transient elevation in serum alanine aminotransferase activity. The ability of VSV to induce a robust multispecific T cell response that controls HBV replication combined with the improved safety profile of the highly attenuated vector suggests that this platform offers a new approach for HBV therapeutic vaccination.

IMPORTANCE A curative treatment for chronic hepatitis B must eliminate the virus from the liver, but current antiviral therapies typically fail to do so. Immune-mediated resolution of infection occurs in a small fraction of chronic HBV patients, which suggests the potential efficacy of therapeutic strategies that boost the patient’s own immune response to the virus. We modified a safe form of VSV to express an immunogenic HBV protein and evaluated the efficacy of this vector in the prevention and treatment of HBV infection in mouse models. Our results show that this vector elicits HBV-specific immune responses that prevent the establishment of HBV infection and reduce viral proteins in the serum and viral DNA/RNA in the liver of mice with persistent HBV replication. These findings suggest that highly attenuated and safe virus-based vaccine platforms have the potential to be utilized for the development of an effective therapeutic vaccine against chronic HBV infection.

    Copyright © 2019 American Society for Microbiology.

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StephenW

一种高度减毒的水泡性口腔炎病毒疫苗平台控制乙型肝炎小鼠模型中的乙型肝炎病毒复制
Safiehkhatoon Moshkani，Carolina Chiale，Sabine M. Lang，John K. Rose，Michael D. Robek
J.-H. James Ou，编辑
DOI：10.1128 / JVI.01586-18

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抽象

治疗性疫苗可以是治疗慢性乙型肝炎病毒（HBV）感染的治疗方案的重要组成部分。我们以前证明表达HBV中表面糖蛋白（MHBs）的重组野生型水泡性口炎病毒（VSV）在HBV复制的小鼠模型中引发功能性免疫应答。然而，VSV具有一些不良的致病性质，并且在人类中使用该平台需要进一步的病毒减毒。因此，我们产生了高度减毒的VSV，其表达MHB并且包含两个减毒突变。评估该载体在小鼠中的免疫原性，发病机理和抗HBV功能。与野生型VSV相比，高度减毒的病毒显示出明显减少的发病机制，但诱导了相似的MHBs特异性CD8 + T细胞和抗体反应。在初始小鼠中由该载体引发的CD8 + T细胞应答阻止了动物中的HBV复制，所述动物随后通过流体动力学注射或用编码HBV基因组的腺相关病毒（AAV-HBV）转导而受到攻击。在通过AAV-HBV转导首次建立持续性HBV复制的小鼠中，随后用减毒的VSV免疫诱导MHBs特异性CD8 + T细胞应答，其对应于血清和肝脏HBV抗原和核酸的减少。 HBV对照与肝内HBV特异性CD8 + T细胞的频率增加和血清丙氨酸氨基转移酶活性的短暂升高有关。 VSV诱导控制HBV复制的强大多特异性T细胞应答的能力与高度减毒载体的改善的安全性特征相结合表明该平台为HBV治疗性疫苗接种提供了新方法。

重要性慢性乙型肝炎的治愈性治疗必须消除肝脏中的病毒，但目前的抗病毒疗法通常不会这样做。免疫介导的感染消退发生在一小部分慢性HBV患者中，这表明治疗策略的潜在功效可以增强患者对病毒的免疫反应。我们修改了安全形式的VSV以表达免疫原性HBV蛋白，并评估了该载体在小鼠模型中预防和治疗HBV感染的功效。我们的研究结果表明，该载体可引发HBV特异性免疫应答，从而阻止HBV感染的建立，并减少血清中的病毒蛋白和持续HBV复制的小鼠肝脏中的病毒DNA / RNA。这些发现表明，高度减毒和安全的基于病毒的疫苗平台有可能被用于开发针对慢性HBV感染的有效治疗性疫苗。

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