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.

项目总结 俄勒冈州国家灵长类研究中心(ONPRC)是七个国家灵长类研究中心之一 由国会于20世纪60年代建立的(全国人民代表大会)。NPRC由NIH主任办公室赞助， 并通过经济高效的方式以独特和必要的方式服务于国家的生物医学研究需求 向联邦资助的国家卫生保健计划和相关的科学专门知识、专门设施和设备提供 对NHP的研究构成了基础研究和人类应用之间至关重要的转换纽带。这个 ONPRC的使命是通过NHP研究计划改善人类健康和生活质量 提高我们对人类疾病原因的认识，并开发有效的预防、治疗、 还有治愈方法。 俄勒冈州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(HHP)，包括 起源于印度的猕猴、日本猕猴、食蟹猴、Hamadrayas和橄榄狒狒，以及一个小的 松鼠猴子的数量。该中心饲养了恒河猴和日本猕猴。其他物种包括 从国内来源进口，以满足项目具体研究需求。 在这项对家长拨款的补充建议中，我们将测试以下假设：1)如果在 吸入雾化中和单抗可预防或减轻SARS-CoV-2 猕猴感染；2)吸入中和单克隆体可减少病毒血症和预防 挑战后给药时的致病机制。为了验证这些假设，我们将测试人类单抗的鸡尾酒。 强大而广泛的SARS-CoV2中和活性，在暴露前保护和/或 限制喷雾剂后的病毒脱落和在喷雾前吸入给药 鼻腔/气管内挑战SARS-CoV-2。将对动物进行病毒学和免疫学跟踪 使用冠状病毒疫苗和治疗制定的标准方案的结果和病理学 评估网络。在尸检时，组织将被采集和处理以进行病毒定量和 组织学。对于暴露后的研究，猕猴将感染SARS-CoV-2，并在一天后接受治疗 用相同的人SARS-CoV-2单抗鸡尾酒，比较不同剂量的气雾剂和静脉给药 剂量。这些原理验证实验将为暴露后的气雾剂治疗铺平道路， 抗体和纳米抗体朝着减少新冠肺炎病的目标迈进。我们的发现将扩大这一实用程序 非人灵长类动物模型的SARS-CoV-2，并将支持发现治疗SARS-CoV-2的新疗法 新冠肺炎，从而实现了P51赠款的主要目的。