Antibody therapeutics for human viral hemorrhagic fevers and prevention of late neurological syndromes

人类病毒性出血热的抗体疗法和预防晚期神经系统综合征

• 批准号: 9212255
• 负责人: Jonathan Abraham
• 金额: $ 44.38万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-22 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9212255
• 关键词: Accounting; Adverse effects; Animal Model; Animals; Antibodies; Antibody Response; Antiviral Agents; Arenavirus; B-Lymphocytes; Binding; Biological Assay; Blood; Blood Donations; Brain; Case Fatality Rates; Cavia; Cell Separation; Cells; Central Nervous System Diseases; Collaborations; Complement; Complex; Cryoelectron Microscopy; Disease; Ebola virus; Electrons; Enrollment; Fc domain; Filovirus; Frankfurt-Marburg Syndrome Virus; Genes; Glycoproteins; Goals; Human; Immune Plasma; Immunology; Infection; Junin virus; Label; Laboratories; Mediating; Membrane; Membrane Glycoproteins; Memory B-Lymphocyte; Methods; Microscopy; Modeling; Molecular; Monoclonal Antibodies; Monoclonal Antibody Therapy; Mus; Natural Killer Cells; Neuraxis; Neurologic; Passive Immunity; Peripheral Blood Mononuclear Cell; Plasma; Prevention; Recombinant Proteins; Recombinants; Recovery; Recruitment Activity; Research; Research Project Grants; Role; Side; Site; Structure; Survivors; Syndrome; Tacaribe Complex Viruses; Testing; Therapeutic antibodies; Transfusion; Vaccines; Viral; Viral Antibodies; Viral Hemorrhagic Fevers; Viral Physiology; Virus; Virus Diseases; Virus Replication; Work; X-Ray Crystallography; advanced disease; base; design; glycoprotein structure; human disease; in vivo; neutralizing antibody; next generation; nonhuman primate; novel strategies; novel therapeutics; pathogen; prevent; response; structural biology; virus development

PROJECT SUMMARY Filoviruses that circulate in the Eastern Hemisphere and several arenaviruses that circulate in the Western hemisphere cause human hemorrhagic fevers with case fatality rates (15% to 90%). Most lack treatment options. The research project proposed here is an effort to use the blood of survivors of viral hemorrhagic fevers to understand the basic molecular features, on both the human host and pathogen side, that make transfusion of antibodies (passive immunity) more or less effective in treating human viral hemorrhagic fevers. To achieve this goal, we propose to compare the human antibody response to filoviruses and arenaviruses. We chose to compare both groups of viruses because for Junín virus infection, transfusion of survivor plasma is highly effective and routinely used clinically – it decreases the case fatality rate of infection to less than 1%. In contrast, while passive immunity has also shown promise in animal models a®gainst Ebola virus, particularly with the use of a three antibody-cocktail called ZMapp , it has yet to be clearly demonstrated as effective in humans. We have recruited survivors of Junín virus, Ebola virus, and Marburg virus infections for blood donation. In Aim 1, we will recover the genes encoding antibodies that react against the arenavirus and filovirus surface glycoprotein (the target of antibodies) from the blood of these survivors. With the sequences of antibody genes, we will produce large quantities of each identified antibody as recombinant proteins and study these in binding and viral neutralization assays. In Aim 2, we will determine antibody-glycoprotein structure using X-ray crystallography and cryo- electron (Cryo-EM) microscopy. In Aim 3, we will study the antibodies' non-neutralizing antiviral activity in cell-based assays and in small animal models working closely with our collaborators. We will also determine if we can alleviate a known side effect of passive immunity against Junín virus – development, in 10% of treated survivors, of a late neurological syndrome that probably occurs because of viral replication in their central nervous system. The basic findings from our research will help us design the next generation of passive immunity strategies against emerging viruses that cause severe human diseases – that is, specifically tailored monoclonal antibody therapies in which purified antibodies of known activity are included.

项目摘要 在东半球循环的丝病毒和几个竞技病毒 在西半球循环引起人类出血的发烧，病例死亡 利率（15％至90％）。大多数缺乏治疗选择。这里提出的研究项目是 努力利用病毒出血狂热的血液来理解基本 分子特征，在人类宿主和病原体方面，都使人输血 抗体（被动免疫史）或多或少有效地治疗人类病毒出血 发烧。为了实现这一目标，我们建议将人类抗体反应比较 丝病毒和体ar虫。我们选择比较两组病毒，因为 Junín病毒感染，生存等离子体的输血非常有效且经常使用 临床上 - 它使感染的病例死亡率降低到小于1％。相比之下， 虽然被动免疫也显示了动物模型A®GainstEbola病毒的希望，但 特别是使用三种称为Zmapp的抗体鸡尾酒，它尚未 清楚地证明在人类中有效。我们已经招募了Junín病毒的生存， 埃博拉病毒和马堡病毒感染用于献血。在AIM 1中，我们将恢复 编码反应背道病毒和丝状病毒表面的抗体的基因 这些冲浪者血液中的糖蛋白（抗体的靶标）。与 抗体基因的序列，我们将产生大量的每种鉴定抗体 作为重组蛋白，并在结合和病毒神经化测定中研究它们。目标 2，我们将使用X射线晶体学和冷冻 - 电子（冷冻EM）显微镜。在AIM 3中，我们将研究抗体的非中和化 基于细胞的测定和与我们的小动物模型中的抗病毒活性 合作者。我们还将确定是否可以减轻被动的已知副作用 对朱恩病毒的免疫力 - 在10％的经过处理的表面上发育 神经系统综合征可能是由于中央病毒复制而发生的 神经系统。我们研究的基本发现将帮助我们设计下一个 针对引起严重的新兴病毒的被动免疫学策略生成 人类疾病 - 也就是说，特别量身定制的单克隆抗体疗法 包括已知活性的纯化抗体。