LAS PROJECT SUMMARY: From a cluster of respiratory illnesses in Wuhan, China, to a worldwide pandemic, the world has learned of a novel coronavirus (SARS-CoV-2) but little is known about the pathogenesis that leads to the disease termed “COVID”. Patients with SARS-CoV-2 infection range from asymptomatic, mild, moderate, to severe infections, resulting in ICU hospitalization and even death. In the US alone, there is a prediction of ~100,000 – 240,000 deaths from SARS-CoV-2 infections. There is an urgent need to 1) characterize the host innate and adaptive response to SARS-CoV-2 and 2) to define immunologic biomarkers that can inform new approaches for diagnostic, prognostic, therapeutic and preventative (e.g., vaccine) modalities in order to improve our ability to treat and prevent disease. To enhance the efficiency of immuophenotyping, the Precision Vaccines Program (PVP) has optimized a number of sample-sparing in vitro assays to characterize both innate and adaptive immune function. These established assays will be applied to the evaluation of SARS-CoV-2 infections and identification of biomarkers associated with morbidity and mortality, which remains an unmet need and a research priority for the fight against COVID. Through investigating soluble and cellular innate and adaptive immune mediators, we will gain insight into the control of inflammation and infection in COVID. In Specific Aim 1 (SA1), we will measure, eg, (a) the plasma enzyme adenosine deaminase (ADA) that metabolizes the anti-inflammatory metabolite adenosine to the immunologically inert inosine, thereby enhancing Th1 immune responses and enhancing antiviral innate and adaptive immunity; and (b) human defensins, antimicrobial peptides that enhance innate antiviral (e.g., IFN) and neutralizing antibody (Ab) responses to coronaviruses. In SA2, we will employ system serology, to further characterize Ab function and efficiency to SARS-CoV-2 across the severity of infection. In SA3, we will measure responses of whole blood leukocytes to activation of pathogen recognition receptors (PRRs) as well as responses of T-cell co-cultures to SARS-CoV-2 spike protein antigen. Overall, successful completion of the proposed IMPACC Local Assay Site studies will provide unique insights into human innate and adaptive immune responses to SARS-CoV-2 in relation to COVID progression and prognosis. These insights will provide fresh approaches to develop diagnostics, therapeutics and preventative measures against COVID-19, including vaccines.