PROJECT SUMMARY The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic has resulted in global morbidity and mortality of dramatic proportions. Although the development of vaccines has occurred at an extremely rapid pace, significant challenges remain including vaccine hesitancy, the development of new variants, and major new outbreaks within several countries, despite best efforts for vaccine production and deployment. In addition, there is an urgent need to be able to address the post-acute sequelae of COVID-19 (PASC) or long haul COVID. Significant health problems, including neurobehavioral, pulmonary, renal, and cardiovascular abnormalities have been observed in both hospitalized and non-hospitalized patients well beyond the acute phase of infection, where replication competent virus is no longer shed. In studies proposed here, we will establish a model for the investigation of the longer-term effects of SARS-CoV- 2 infection in African green monkeys (AGM) supported by our previous observations during the acute phase of infection. In the context of our research strategy, we will perform clinical, biologic, immunologic, virologic, behavioral, pulmonary (plethysmography) and telemetric studies at baseline and during the course of our studies. The first six weeks of SARS-CoV-2 infection will be investigated within our Regional Biocontainment Laboratory at BSL- 3. At six weeks post-infection, we will evaluate the status of active and transmissible infection to support the safe transfer of animals to a BSL-2+ environment for an additional 12 weeks, where we will study the longer-term consequences of SARS-CoV-2 infection. Necropsies will be performed within BSL-3 as a safety precaution. Considerable anecdotal and survey evidence suggests vaccination of persons with PASC symptoms can be mitigated in whole or in part by the administration of vaccines approved under emergency use authorization. Our studies will investigate the administration of the Pfizer vaccine to animals two days post-infection to determine its potential as a therapeutic vaccine to modulate the acute and post-acute infection phases. We will also evaluate the potential of a Cathepsin-L inhibitor that interferes with cell entry of SARS-CoV-2 infection. Our previous collaborative studies with Selva Therapeutics, Inc, suggests virological and immunologic properties with earlier detection of neutralizing antibodies in AGM. We anticipate the proposed studies may provide urgently needed novel, translatable, and actionable approaches for the modulation of COVID-19 disease in humans.