Human neutralizing antibodies for Zika virus

寨卡病毒的人类中和抗体

• 批准号: 9219776
• 负责人: James E Crowe
• 金额: $ 132.79万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9219776
• 关键词: Adult; Aedes; Affinity; Africa; Americas; Antibodies; Antibody Therapy; Arboviruses; Area; Arthralgia; Asia; B-Lymphocytes; Binding; Biological Assay; Brazil; Central America; Characteristics; Congenital Abnormality; Conjunctivitis; Country; Culicidae; Dengue; Dengue Infection; Development; Diagnostic; Disease; Disease Outbreaks; Donor Selection; Epidemic; Epitopes; Exanthema; Fever; Flavivirus; Future; Generations; Glycoproteins; Goals; Government; Guillain-Barré Syndrome; Headache; Human; Humoral Immunities; IgG Receptors; Immune; Immunity; Immunoglobulin G; Immunologics; Immunotherapeutic agent; Individual; Infant; Infection; Interferometry; International; Latin American; Lead; Link; Location; Mediating; Mexico; Microcephaly; Micronesia; Molecular; Molecular Conformation; Molecular Genetics; Monitor; Monoclonal Antibodies; Mothers; Mus; Mutagenesis; Myalgia; Myeloid Cells; Neonatal; Newborn Infant; Pathogenesis; Pathogenicity; Pattern; Pharmaceutical Preparations; Phenotype; Pre-Clinical Model; Pregnancy; Pregnant Women; Proteins; Public Health; Reporting; Serologic tests; Site; South America; Specificity; Surface Plasmon Resonance; Survivors; Technetium Tc 99m ciprofloxacin; Technology; Testing; Therapeutic; Therapeutic Agents; Travel; Vaccination; Vaccines; Variant; Viral; Virion; Virus; Virus Diseases; Virus Replication; Woman; Work; World Health Organization; Zika Virus; Zika virus vaccine; chikungunya; comparative efficacy; cross reactivity; env Gene Products; human monoclonal antibodies; in vivo; inhibiting antibody; mouse model; multidisciplinary; neutralizing antibody; neutralizing monoclonal antibodies; prophylactic; public health emergency; receptor binding; screening; secondary infection; transmission process; virus pathogenesis

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.

寨卡病毒（Zikv）是一种新兴的蚊子传播黄病毒，已成为全球公众 健康威胁。世界卫生组织宣布ZIKV及其与先天缺陷的疑似联系 2016年2月1日，国际公共卫生紧急情况。ZIKV感染的流行病已经 我们在墨西哥以及中美洲和南美都有报道，并与Guillain-Barre案有关 成年人的综合征和新生婴儿的小头畸形在孕产妇感染期间 怀孕。尽管有可能感染并引起数百万的疾病，但特定的诊断，但 无法获得治疗或ZIKV疫苗。这种合作的主要目标和 互动项目是定义新近的分子，遗传，免疫学特征 孤立的中和人mab具有广泛特异性，针对所有ZIKV菌株。第二个目标 是通过中和mAb来定义保护的机械相关性。第三个目标是 确定与ZIKV结合的交叉反应性抗Denv人mab是 在新开发的ZIKV小鼠模型中，保护性/治疗或致病性。我们假设 潜在的抑制性mAb识别与关键ZIKV结构过渡相关的表位 在进入过程中，具有高亲和力并阻止一个或多个钥匙步骤（例如，附件，输入或融合）。 我们的方法将包括人物mAB的高效率隔离和详细的功能 和结构分析以定义人体mAb抑制ZIKV的方式以及为什么。我们还将探索 FCR结合的意义并确定ZIKV是否与DENV相似或不同 抗体介导的疾病免疫增强的背景。除了基本 ZIKV发病机理和免疫力的研究，这些研究还将导致生成 可以在临床前模型中测试的一组完全人类的mAb，可以快速开发 作为人类的治疗或预防性生物药物。该项目的研究也将告知 持续的诊断和未来的疫苗针对ZIKV的工作将定义主要专业 与潜在类型特异性抗体介导的病毒相关的抗原位点的表位 谈判和保护。合作的多学科小组集会 在此多PI应用程序中的研究已经有效地合作，并具有很强的记录 研究粉丝，基孔肯亚和其他节肢动物传播病毒，并有明确的分裂 在本应用中提出的研究的劳动。