A protective Zika virus E-dimer-based subunit vaccine engineered to abrogate antibody-dependent enhancement of dengue infection.,Nature Immunology

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A protective Zika virus E-dimer-based subunit vaccine engineered to abrogate antibody-dependent enhancement of dengue infection.
Nature Immunology ( IF 27.7 ) Pub Date : 2019-09-02 , DOI: 10.1038/s41590-019-0477-z
Jose Luis Slon-Campos ₁ , Wanwisa Dejnirattisai ₁ , Brett W Jagger _{2,

3} , César López-Camacho ₄ , Wiyada Wongwiwat ₁ , Lorellin A Durnell ₂ , Emma S Winkler ₂ , Rita E Chen ₂ , Arturo Reyes-Sandoval ₄ , Felix A Rey _{5,

6} , Michael S Diamond _{2,

7,

8,

9} , Juthathip Mongkolsapaya _{1,

10} , Gavin R Screaton ₁₁

Affiliation

Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
Department of Medicine, Washington University School of Medicine, Saint Louis, MO, USA.
Department of Medicine, Western Michigan University Homer Stryker MD School of Medicine, Kalamazoo, MI, USA.
Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
Unité de Virologie Structurale, Département de Virologie, Institut Pasteur, Paris, France.
Centre National de la Recherche Scientifique, Unité Mixte de Recherche 3569, Paris, France.
Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO, USA.
Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, MO, USA.
Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, Saint Louis, MO, USA.
Dengue Hemorrhagic Fever Research Unit, Office for Research and Development, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand.
Division of Medical Sciences, University of Oxford, Oxford, UK.

Infections with dengue virus (DENV) and Zika virus (ZIKV) can induce cross-reactive antibody responses. Two immunodominant epitopes-one to precursor membrane protein and one to the fusion loop epitope on envelope (E) protein-are recognized by cross-reactive antibodies1-3 that are not only poorly neutralizing, but can also promote increased viral replication and disease severity via Fcγ receptor-mediated infection of myeloid cells-a process termed antibody-dependent enhancement (ADE)1,4,5. ADE is a significant concern for both ZIKV and DENV vaccines as the induction of poorly neutralizing cross-reactive antibodies may prime an individual for ADE on natural infection. In this report, we describe the design and production of covalently stabilized ZIKV E dimers, which lack precursor membrane protein and do not expose the immunodominant fusion loop epitope. Immunization of mice with ZIKV E dimers induces dimer-specific antibodies, which protect against ZIKV challenge during pregnancy. Importantly, the ZIKV E-dimer-induced response does not cross-react with DENV or induce ADE of DENV infection.

中文翻译：

一种保护性寨卡病毒基于 E-二聚体的亚单位疫苗，旨在消除对登革热感染的抗体依赖性增强。

登革热病毒 (DENV) 和寨卡病毒 (ZIKV) 感染可诱导交叉反应性抗体反应。两个免疫显性表位——一个是前体膜蛋白，一个是包膜 (E) 蛋白上的融合环表位——被交叉反应性抗体 1-3 识别，这些抗体不仅中和性差，而且还可以通过以下途径促进病毒复制和疾病严重程度的增加Fcγ 受体介导的骨髓细胞感染 - 一个称为抗体依赖性增强 (ADE)1,4,5 的过程。ADE 是 ZIKV 和 DENV 疫苗的一个重要问题，因为中和性差的交叉反应性抗体的诱导可能会导致个体在自然感染时出现 ADE。在本报告中，我们描述了共价稳定 ZIKV E 二聚体的设计和生产，其缺乏前体膜蛋白并且不暴露免疫显性融合环表位。用 ZIKV E 二聚体对小鼠进行免疫可诱导二聚体特异性抗体，从而在怀孕期间防止 ZIKV 攻击。重要的是，ZIKV E-二聚体诱导的反应不会与 DENV 发生交叉反应或诱导 DENV 感染的 ADE。

更新日期：2019-09-03

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