Novel Therapy for SARS-CoV-2 Virus Infection and Pathogenesis by Aerosol Delivery of Monoclonal Antibodies

通过单克隆抗体气溶胶递送治疗 SARS-CoV-2 病毒感染和发病机制的新疗法

基本信息

批准号：
10400511
负责人：
Peter Gordon Barr-Gillespie
金额：
$ 49.96万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10400511
关键词：
2019-nCoV Aerosols Animal Housing Animals Antibodies Antibody Therapy Antibody titer measurement Autopsy Basic Science Biomedical Research Blood Breeding COVID-19 COVID-19 mortality COVID-19 pandemic COVID-19 prevention COVID-19 therapeutics COVID-19 treatment Caring Clinical Clinical Trials Collaborations Congresses Containment Core Grant Coronavirus Coronavirus Infections Development Devices Disease Dose Effectiveness Equipment Evaluation Failure Freeze Drying Funding Goals Grant Harvest Health Histology Home Hour Human Immunoglobulin A Immunoglobulin M Immunologics Immunology Immunotherapeutic agent Individual Infant Infection Infusion procedures Inhalation Inhalation Drug Administration Intraperitoneal Injections Intravenous Japanese Monkey Knowledge Laboratory Animals Link Lung Macaca Macaca fascicularis Macaca mulatta Medical Methods Mission Modeling Monoclonal Antibodies Mucous Membrane Mus Nebulizer Nose Oregon Outcome Papio anubis Particle Size Pathogenesis Pathology Patients Prevention Primates Process Protocols documentation Quality of life Rattus Research Resistance Respiratory Syncytial Virus Infections Respiratory System Respiratory syncytial virus Risk SARS-CoV-2 antibody SARS-CoV-2 infection SARS-CoV-2 spike protein SARS-CoV-2 variant Safety Saimiri Sampling Savings Site Social Distance Source Specificity Standardization Streptococcus pneumoniae Surface Symptoms Testing Therapy Evaluation Time Tissues Topical application United States National Institutes of Health Vaccines Variant Viral Pathogenesis Viremia Virus Virus Diseases Virus Shedding adaptive immunity advanced disease aerosolized convalescent plasma coronavirus vaccine cost cost effective experimental study human disease human monoclonal antibodies immunoprophylaxis improved individual variation influenza infection nanobodies nasal swab neutralizing monoclonal antibodies nonhuman primate novel novel strategies novel therapeutics oropharyngeal swab pandemic disease parent grant passive antibodies passive immunoprophylaxis polyclonal antibody prevent programs vaccine evaluation viral RNA virology

项目摘要

PROJECT SUMMARY The Oregon National Primate Research Center (ONPRC) is one of seven National Primate Research Centers (NPRCs) established by Congress in the 1960s. The NPRCs are sponsored by the NIH Office of the Director, and serve the nation's biomedical research needs in a unique and essential fashion through cost-effective provision of NHPs and related scientific expertise, specialized facilities, and equipment to federally funded studies of NHPs that comprise a vital translational link between basic research and human applications. The mission of the ONPRC is to improve human health and the quality of life through NHP research programs that advance our knowledge of the causes of human diseases and that develop effective preventions, treatments, and cures. The Oregon National Primate Research Center (ONPRC) P51 Core Grant (P51-OD011092) supports a colony of approximately 4900 breeding and research nonhuman primates (NHPs), including rhesus macaques of Indian origin, Japanese macaques, cynomolgus macaques, Hamadrayas and olive baboons, and a small number of squirrel monkeys. Rhesus and Japanese macaques are bred at the Center. Other species are imported from domestic sources to fulfill project specific research needs. In this supplement proposal to the parent grant, we will test the hypotheses that: 1) When given prior to challenge, inhaled, aerosolized neutralizing monoclonal antibodies can prevent or mitigate SARS-CoV-2 infection in rhesus macaques; and 2) Inhaled neutralizing monoclonals can reduce viremia and prevent pathogenesis when given after challenge. To test these hypotheses, we will test a cocktail of human mAbs with potent and broad SARS-CoV2-neutralizing activity for their effectiveness in pre-exposure protection and/or limitation of viral shedding following aerosolization and administration by inhalation prior to intranasal/intratracheal challenge with SARS-CoV-2. Animals will be followed for virological and immunological outcomes and pathology using standard protocols developed by the Coronavirus Vaccines and Therapy Evaluation Network. At necropsy, tissues will be harvested and processed for virus quantification and histology. For post-exposure studies, macaques will be infected with SARS-CoV-2, and treated one day later with the same cocktail of human SARS-CoV-2 mAbs, comparing aerosol and intravenous delivery at various doses. These proof-of-principle experiments will pave the way for post-exposure aerosol treatments with potent antibodies and nanobodies toward the goal of reducing COVID-19 disease. Our findings will expand the utility of the nonhuman primate model for SARS-CoV-2 and will support the discovery of novel therapeutics for COVID-19, thereby fulfilling the primary purpose of the P51 grant.

项目摘要俄勒冈国家灵长类动物研究中心（ONPRC）是七个国家灵长类动物研究中心之一（NPRC）由国会于1960年代建立。 NPRC是由NIH主任办公室赞助的并通过具有成本效益的独特而基本的方式满足国家的生物医学研究需求为联邦资助的NHP及相关科学专业知识，专业设施和设备提供 NHP的研究包括基础研究与人类应用之间的重要翻译联系。这 ONPRC的使命是通过NHP研究计划改善人类健康和生活质量促进我们对人类疾病原因的了解，并发展有效的预防，治疗，和治疗。俄勒冈州国家灵长类动物研究中心（ONPRC）P51核心赠款（P51-OD011092）支持一个殖民地大约4900种繁殖和研究非人类灵长类动物（NHP），包括恒河猕猴印度起源，日本猕猴，cynomolgus猕猴，hamadrayas和橄榄狒狒，以及一个小的松鼠猴子的数量。恒河猴和日本猕猴在中心繁殖。其他物种是从国内进口来满足项目特定的研究需求。在对父母赠款的补充提案中，我们将测试以下假设：1）挑战，吸入，雾化的中和单克隆抗体可以预防或减轻SARS-COV-2 猕猴感染； 2）吸入中和单克隆可以降低病毒血症并防止挑战后发病机理。为了检验这些假设，我们将用有效且广泛的SARS-COV2中和活动在暴露前保护和/或在吸入之前的气化和给药后，病毒脱落的限制 SARS-COV-2带有鼻内/气管内挑战。病毒学和免疫学的动物将被遵循使用冠状病毒疫苗开发的标准方案的结果和病理学评估网络。在尸检时，将收集组织并处理以进行病毒定量和组织学。对于暴露后研究，猕猴将被SARS-COV-2感染，并在一天后治疗与人类SARS-COV-2 mAb相同的鸡尾酒，比较各种气溶胶和静脉输送剂量。这些原则证明实验将为暴露后的气溶胶处理铺平道路抗体和纳米型降低了Covid-19疾病的目标。我们的发现将扩大公用事业 SARS-COV-2的非人类灵长类动物模型，并将支持发现新型治疗剂的 Covid-19，从而实现了p51赠款的主要目的。