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.