Discovery and characterization of protective Influenza Type B Virus neuraminidase antibodies

保护性 B 型流感病毒神经氨酸酶抗体的发现和表征

基本信息

批准号：
10782120
负责人：
Rachael Wolters
金额：
$ 12.29万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10782120
关键词：
Air Animal Model Animals Antibodies Antibody Therapy Antiviral Agents Binding Biological Biological Assay Biological Models Biological Products Biophysics Bronchopneumonia COVID-19 pandemic Cell Culture Techniques Cell Line Cells Cessation of life Childhood Clinical Trials Complex Disease Drug Delivery Systems Elderly Environment Enzyme-Linked Immunosorbent Assay FDA approved Family Ferrets Glycoproteins Goals Health Health Professional Hemagglutinin Human Immune response Immunoglobulin A Immunoglobulin G In Vitro Industry Infection Influenza Influenza A virus Influenza B Virus Intramuscular Intramuscular Injections Intravenous Intravenous infusion procedures K-Series Research Career Programs Knowledge Laboratory Research Liquid substance Longevity Lung Membrane Glycoproteins Mentors Methods Modality Modeling Monoclonal Antibodies Morbidity - disease rate Mucous Membrane Mucous body substance Nebulizer Neuraminidase Neuraminidase inhibitor Nucleoproteins Orthomyxoviridae Pathogenesis Pathology Pharmaceutical Preparations Phylogenetic Analysis Physicians Physiological Play Population Positioning Attribute Preclinical Testing Program Development Proteins Public Health Recombinants Recording of previous events Research Respiratory Disease Respiratory Mucosa Role Scientist Seasons Sialic Acids Site Stains Study models Surface System Techniques Testing Therapeutic Therapeutic Agents Therapeutic Monoclonal Antibodies Therapeutic antibodies Tight Junctions Tissue Model Topical application Training Translating Transmission Electron Microscopy Vaccination Vaccine Design Vaccinee Vaccines Veterinarians Viral Viral Load result Viral Pathogenesis Virion Virus Virus Diseases Virus Replication Virus Shedding Visualization Vulnerable Populations Work aerosolized airway epithelium animal model development biophysical properties career career development cell immortalization compliance behavior drug candidate drug discovery drug efficacy drug testing druggable target efficacy evaluation experience follow-up human monoclonal antibodies human tissue improved in vitro Assay in vitro testing in vivo influenza infection influenza virus vaccine influenzavirus insight interest intraperitoneal member mouse model novel novel strategies pandemic disease pandemic potential pre-clinical prevent professor prophylactic receptor respiratory virus response seasonal influenza skill acquisition structural biology therapeutic candidate translational applications transmission process vaccine development vaccinology

项目摘要

Project Summary/Abstract Influenza causes an estimated 1 billion cases yearly, with severe cases leading to fatal bronchopneumonia, particularly in vulnerable populations. Influenza virions express two major surface glycoproteins, hemagglutinin (HA) and neuraminidase (NA), the latter of which is of interest due to its role in viral egress and cleavage from mucus. Currently, the only FDA-approved antivirals used to treat influenza are neuraminidase inhibitors, which are ineffective against some strains. Monoclonal antibodies (mAbs) directed at NA provide an alternative therapeutic candidate. Delivering NA mAbs to the respiratory mucosal surface, where the virus replicates, is a novel delivery method that could improve drug efficacy and patient compliance. This five-year research career development award will provide training and development of the skills necessary for the candidate to establish an independent research laboratory focused on understanding how human antibodies against influenza can be harnessed to treat and prevent disease and transmission in animal models. Currently, the candidate is a veterinarian and a graduate trainee at the Vanderbilt Vaccine Center who will transition to an assistant professor position on the physician-scientist track in July 2024. Her training to date has focused on the isolation and characterization of human monoclonal antibodies (mAbs) from subjects with prior influenza history and mouse models of therapy. She will supplement this experience with further training in developing in vivo ferret and ex vivo human tissue models of influenza infection with which to study the natural pathogenesis of this virus and how human mAbs bind influenza to reduce pathogenesis. The short- term goals of the proposed studies are to test the central hypothesis that neuraminidase-directed antibodies play a significant role in the protective immune response and can be harnessed with antibody therapeutics. This training will be supported by mentoring from national experts in the study of human antibodies (James Crowe, Jr., Ivelin Georgiev), human airway epithelial cultures (Timothy Blackwell), influenza vaccinology (Spyros Kalams), and small animal models of virus infection and pathology (Katherine Gibson-Corley). The applicant aims to 1) elucidate the mechanisms of influenza type B (IBV) inhibition by mAbs specific to the neuraminidase (NA) glycoprotein to test the hypotheses that NA antibodies exert distinct mechanisms of protection, 2) use a human airway model of IBV infection to determine how NA mAbs in the presence of mucus behave, 3) and test these mAbs in a ferret model of intranasal delivery to test the hypothesis that NA mAbs delivered topically can reduce viral load and shedding. Overall, these studies will help define the role of IBV NA antibodies and the mechanism of delivering mAbs to the respiratory mucosal surface. Industry groups are developing protective mAbs made by the candidate as human therapeutic agents. Thus, these studies directly translate the importance of human health and contribute to a more fundamental understanding of the disease.

项目概要/摘要流感每年造成约10亿例病例，严重病例会导致死亡支气管肺炎，特别是在弱势人群中。流感病毒颗粒表达两个主要表面糖蛋白、血凝素 (HA) 和神经氨酸酶 (NA)，后者因其在病毒从粘液中排出和裂解。目前，FDA 批准的唯一用于治疗流感的抗病毒药物是神经氨酸酶抑制剂，对某些菌株无效。单克隆抗体（mAb）针对 NA 提供了替代治疗候选者。将 NA mAb 递送至呼吸道粘膜表面，病毒在其中复制，是一种新颖的递送方法，可以提高药物疗效和患者依从性。这个为期五年的研究职业发展奖将提供必要技能的培训和发展让候选人建立一个独立的研究实验室，专注于了解人类如何流感抗体可用于治疗和预防动物疾病和传播模型。目前，该候选人是范德比尔特疫苗中心的兽医和研究生实习生，将于 2024 年 7 月转任医师科学家助理教授职位。她接受的培训日期重点是从受试者中分离和表征人单克隆抗体 (mAb) 具有既往流感病史和小鼠治疗模型。她将进一步补充这一经验开发用于研究的流感感染体内雪貂和离体人体组织模型的培训该病毒的自然发病机制以及人类单克隆抗体如何结合流感病毒以减少发病机制。短- 拟议研究的长期目标是检验神经氨酸酶导向抗体的中心假设在保护性免疫反应中发挥重要作用，可以通过抗体疗法加以利用。该培训将得到人类抗体研究国家专家的指导（James Crowe, Jr.、Ivelin Georgiev)、人类气道上皮培养 (Timothy Blackwell)、流感疫苗学（Spyros Kalams）和病毒感染和病理学的小动物模型（Katherine Gibson-Corley）。这申请人的目标是 1) 阐明针对 B 型流感 (IBV) 的单克隆抗体抑制机制神经氨酸酶 (NA) 糖蛋白，用于测试 NA 抗体发挥不同机制的假设保护，2) 使用 IBV 感染的人类气道模型来确定 NA mAb 在粘液存在下的作用行为，3) 并在雪貂鼻内递送模型中测试这些 mAb，以检验 NA mAb 的假设局部给药可以减少病毒载量和脱落。总体而言，这些研究将有助于明确 IBV NA 的作用抗体以及将单克隆抗体递送至呼吸道粘膜表面的机制。行业团体有开发由候选人生产的保护性单克隆抗体作为人类治疗剂。因此，这些研究直接转化人类健康的重要性并有助于对该疾病有更基本的了解。