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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结