Human neutralizing antibodies for Zika virus

寨卡病毒(Zika Virus，ZIKV)是一种新兴的蚊媒黄病毒，已成为全球公众 对健康的威胁。世界卫生组织宣布ZIKV及其疑似与出生缺陷有关 2016年2月1日，一场国际突发公共卫生事件。寨卡病毒感染的流行已经 在墨西哥、中美洲和南美洲有报道，并与格林-巴利病例有关 在母体感染的情况下，成人综合征和新生儿小头畸形 怀孕了。尽管有可能感染数百万人并导致疾病，但特定的诊断方法， 目前还没有针对ZIKV的治疗方法或疫苗。这项协作和 互动项目是定义分子，遗传，免疫学，新的- 分离出对所有ZIKV毒株具有广泛特异性的中和性人单抗。第二个目标 是通过中和mAbs来定义保护的机械性关联。第三个目标是 确定与ZIKV结合的交叉反应抗DENV人源单抗是否 新开发的ZIKV小鼠模型的保护性/治疗性或致病性。我们假设 有效抑制单抗识别与关键ZIKV结构转变相关的表位 具有高亲和力，并且在进入(例如，连接、进入或融合)期间阻止一个或多个密钥步骤。 我们的方法将包括高效分离人单抗，并具有详细的功能 以及结构分析，以确定人类单抗如何以及为什么抑制ZIKV。我们还将探索 Fc？R结合的意义并确定ZIKV与DENV在 抗体介导的免疫增强疾病的背景。除了基本功能之外 对寨卡病毒致病机理和免疫的研究，这些研究也将导致产生 一组可在临床前模型中进行测试并可快速发展的全人mAbs 作为人类的治疗或预防生物药物。这个项目的研究也将告诉我们 正在进行的针对ZIKV的诊断和未来疫苗工作，因为它们将确定主要的主要 与强效类型特异性抗体介导型病毒相关的抗原表位 中和和保护。协作的多学科小组聚集在一起进行 在这一多PI应用程序中的研究已经进行了富有成效的协作，在 研究登革热、基孔肯雅和其他节肢动物传播的病毒，并有明确的划分 为本申请中建议的研究工作。

Zika virus (ZIKV) is an emerging mosquito-transmitted flavivirus that has become a global public health threat. The World Health Organization declared ZIKV and its suspected link to birth defects an international public health emergency on February 1, 2016. Epidemics of ZIKV infection have been reported in Mexico, and Central and South America and linked to cases of Guillain-Barre syndrome in adults and microcephaly in newborn infants in the setting of maternal infection during pregnancy. Despite the potential for infecting and causing disease in millions, specific diagnostics, treatments, or vaccines for ZIKV are not available. The primary goal of this collaborative and interactive project is to define the molecular, genetic, immunologic, characteristics of newly- isolated neutralizing human mAbs with broad specificity against all strains of ZIKV. A second goal is to define the mechanistic correlates of protection by neutralizing mAbs. A third goal is to determine whether cross-reactive anti-DENV human mAbs that bind to ZIKV are protective/therapeutic or pathogenic in a newly developed mouse model of ZIKV. We hypothesize that potently inhibitory mAbs recognize epitopes associated with key ZIKV structural transitions with high affinity and block one or more keys step during entry (e.g., attachment, entry, or fusion). Our approach will include high-efficiency isolation of human mAbs and with detailed functional and structural analyses to define how and why human mAbs inhibit ZIKV. We also will explore the significance of Fc?R binding and determine whether ZIKV is similar or different than DENV in the context of antibody-mediated immune enhancement of disease. In addition to fundamental studies of ZIKV pathogenesis and immunity, these studies also will result in the generation of a group of fully human mAbs that can be tested in preclinical models and could be developed rapidly as therapeutic or prophylactic biologic drugs for humans. Studies in this project also will inform ongoing diagnostic and future vaccine efforts against ZIKV, as they will define the principal major antigenic sites epitopes associated with potent type-specific antibody-mediated virus neutralization and protection. The collaborative multidisciplinary group assembled to conduct studies in this multi-PI application already collaborates productively, with a strong track record in studies of dengue, chikungunya and other arthropod-borne viruses, and has a clear division of labor for the studies proposed in this application.