Human neutralizing antibodies for Zika virus

寨卡病毒的人类中和抗体

• 批准号: 10082297
• 负责人: James E Crowe
• 金额: $ 65.52万
• 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 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10082297
• 关键词: Adult; Aedes; Affinity; Africa; Americas; Antibodies; Antibody Therapy; Arboviruses; Area; Arthralgia; Asia; B-Lymphocytes; Binding; Biological; 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; Serology test; Site; South America; Specificity; Structure; Surface Plasmon Resonance; Survivors; Technetium Tc 99m ciprofloxacin; Technology; Testing; Therapeutic; Therapeutic Agents; Travel; Vaccination; Vaccines; Variant; Viral; Viral Pathogenesis; Virion; Virus; Virus Diseases; Virus Replication; Woman; Work; World Health Organization; ZIKA; ZIKV disease; ZIKV infection; Zika Virus; Zika virus vaccine; chikungunya; comparative efficacy; cross reactivity; env Gene Products; human monoclonal antibodies; in vivo; inhibiting antibody; mosquito-borne; mouse model; multidisciplinary; neutralizing antibody; neutralizing monoclonal antibodies; prophylactic; public health emergency; receptor binding; screening; secondary infection; severe dengue; transmission process

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）是一种新兴的由蚊子传播的黄病毒，已成为全球公众关注的焦点。 健康威胁。世界卫生组织宣布寨卡病毒及其与出生缺陷的疑似关联 2016 年 2 月 1 日，国际公共卫生紧急事件。寨卡病毒感染流行 在墨西哥、中美洲和南美洲均有报道，并与吉兰-巴利病例有关 产妇感染期间成人综合征和新生儿小头畸形 怀孕。尽管有可能感染并导致数百万人患病，但具体的诊断， 目前还没有寨卡病毒的治疗方法或疫苗。此次合作的主要目标是 互动项目是为了定义新的分子、遗传、免疫学特征 分离的中和人单克隆抗体，对所有寨卡病毒株具有广泛的特异性。第二个进球 的目的是通过中和单克隆抗体来定义保护的机制相关性。第三个目标是 确定与 ZIKV 结合的交叉反应性抗 DENV 人单克隆抗体是否 在新开发的 ZIKV 小鼠模型中具有保护性/治疗性或致病性。我们假设 强效抑制性单克隆抗体可识别与 ZIKV 关键结构转变相关的表位 具有高亲和力并阻止进入过程中的一个或多个关键步骤（例如，附着、进入或融合）。 我们的方法将包括人类单克隆抗体的高效分离和详细的功能 以及结构分析，以确定人类单克隆抗体如何以及为何抑制 ZIKV。我们还将探索 Fc?R 结合的重要性并确定 ZIKV 与 DENV 是否相似或不同 抗体介导的疾病免疫增强的背景。除了基础的 ZIKV 发病机制和免疫的研究，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开发的全人源单克隆抗体 作为人类的治疗或预防性生物药物。该项目的研究还将提供信息 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目标 与强效类型特异性抗体介导的病毒相关的抗原位点表位 中和和保护。多学科协作小组聚集在一起进行 在这个多 PI 应用程序中的研究已经进行了富有成效的合作，并在以下方面拥有良好的记录： 登革热、基孔肯雅热和其他节肢动物传播的病毒的研究，并有明确的划分 为本申请中提出的研究工作。

项目成果

TMPRSS2 and TMPRSS4 promote SARS-CoV-2 infection of human small intestinal enterocytes.

TMPRSS2 和 TMPRSS4 促进人小肠肠细胞的 SARS-CoV-2 感染。

• 发表时间: 2020-05-13
• 影响因子: 24.8
• 作者: Zang, Ruochen;Gomez Castro, Maria Florencia;McCune, Broc T;Zeng, Qiru;Rothlauf, Paul W;Sonnek, Naomi M;Liu, Zhuoming;Brulois, Kevin F;Wang, Xin;Greenberg, Harry B;Diamond, Michael S;Ciorba, Matthew A;Whelan, Sean P J;Ding, Siyuan
• 通讯作者: Ding, Siyuan

Identification of SARS-CoV-2 spike mutations that attenuate monoclonal and serum antibody neutralization.

鉴定减弱单克隆抗体和血清抗体中和作用的 SARS-CoV-2 尖峰突变。

• 发表时间: 2021-03-10
• 影响因子: 30.3
• 作者: Liu, Zhuoming;VanBlargan, Laura A;Bloyet, Louis;Rothlauf, Paul W;Chen, Rita E;Stumpf, Spencer;Zhao, Haiyan;Errico, John M;Theel, Elitza S;Liebeskind, Mariel J;Alford, Brynn;Buchser, William J;Ellebedy, Ali H;Fremont, Daved H;Diamond, M
• 通讯作者: Diamond, M

Replication-Competent Vesicular Stomatitis Virus Vaccine Vector Protects against SARS-CoV-2-Mediated Pathogenesis in Mice.

具有复制能力的水泡性口炎病毒疫苗载体可预防小鼠中 SARS-CoV-2 介导的发病机制。

• 发表时间: 2020-09-09
• 影响因子: 30.3
• 作者: Case, James Brett;Rothlauf, Paul W;Chen, Rita E;Kafai, Natasha M;Fox, Julie M;Smith, Brittany K;Shrihari, Swathi;McCune, Broc T;Harvey, Ian B;Keeler, Shamus P;Bloyet, Louis;Zhao, Haiyan;Ma, Meisheng;Adams, Lucas J;Winkler, Emma S;Holt
• 通讯作者: Holt

Publisher Correction: SARS-CoV-2 infection of human ACE2-transgenic mice causes severe lung inflammation and impaired function.

出版商更正：人类 ACE2 转基因小鼠的 SARS-CoV-2 感染会导致严重的肺部炎症和功能受损。

• 发表时间: 2020-11
• 影响因子: 30.5
• 作者: Winkler, Emma S;Bailey, Adam L;Kafai, Natasha M;Nair, Sharmila;McCune, Broc T;Yu, Jinsheng;Fox, Julie M;Chen, Rita E;Earnest, James T;Keeler, Shamus P;Ritter, Jon H;Kang, Liang;Dort, Sarah;Robichaud, Annette;Head, Richard;Holtzman, Michae
• 通讯作者: Holtzman, Michae

The Challenges of Vaccine Development against a New Virus during a Pandemic.

大流行期间针对新病毒的疫苗开发面临的挑战。

• 发表时间: 2020
• 影响因子: 30.3
• 作者: Diamond, Michael S;Pierson, Theodore C
• 通讯作者: Pierson, Theodore C