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

• 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
• 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

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.

项目概要 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 20 世纪 60 年代设立。 NPRC 由 NIH 主任办公室赞助， 并通过具有成本效益的方式以独特且重要的方式满足国家生物医学研究需求 向联邦资助的 NHP 和相关科学专业知识、专门设施和设备提供 NHP 的研究构成了基础研究和人类应用之间重要的转化联系。这 ONPRC 的使命是通过 NHP 研究项目改善人类健康和生活质量， 增进我们对人类疾病原因的了解，并制定有效的预防、治疗、 并治愈。 俄勒冈国家灵长类研究中心 (ONPRC) P51 核心拨款 (P51-OD011092) 支持一个群体 大约 4900 只繁殖和研究非人类灵长类动物 (NHP)，包括恒河猴 印度原产地、日本猕猴、食蟹猴、狒狒和橄榄狒狒，以及小型狒狒 松鼠猴的数量。该中心饲养着恒河猴和日本猕猴。其他物种有 从国内进口以满足项目特定研究需求。 在这份针对家长补助金的补充提案中，我们将测试以下假设： 1) 在 攻击、吸入、雾化中和单克隆抗体可以预防或减轻 SARS-CoV-2 恒河猴感染； 2) 吸入中和单克隆抗体可以减少病毒血症并预防 攻击后给予的发病机制。为了检验这些假设，我们将测试人类单克隆抗体的混合物 有效且广泛的 SARS-CoV2 中和活性，可有效发挥暴露前保护作用和/或 雾化和吸入给药后病毒脱落的限制 SARS-CoV-2 鼻内/气管内攻击。将跟踪动物进行病毒学和免疫学检测 使用冠状病毒疫苗和治疗开发的标准方案进行结果和病理学分析 评价网．在尸检时，将收集并处理组织以进行病毒定量和 组织学。对于暴露后研究，猕猴将感染 SARS-CoV-2，并在一天后接受治疗 使用相同的人类 SARS-CoV-2 mAb 混合物，比较不同情况下的气雾剂和静脉注射 剂量。这些原理验证实验将为有效的暴露后气溶胶治疗铺平道路 抗体和纳米抗体以减少 COVID-19 疾病的目标。我们的发现将扩大实用性 SARS-CoV-2 的非人类灵长类动物模型的建立，并将支持新疗法的发现 COVID-19，从而实现了 P51 拨款的主要目的。