CORALE-SeroNet Project 1

ABSTRACT Pressing questions pertain to the consistently observed paradoxes regarding the variable nature of host susceptibility and response to SARS-CoV-2. We and others have reported on more active spread and greater morbidity among older persons and ethnic/racial minorities, especially with certain comorbidities and metabolic. To date the evidence to date suggests that while some individuals exhibit a particular vulnerability to SARS-CoV- 2 (i.e. susceptibility), many others have an intrinsic or acquired relative immunity (i.e. resistance) to infection or disease risk or both for unknown reasons. Further compounding the enigmatic nature of SARS-CoV-2 risk is the conflicting data on measures of immunity. We and others have found that the extent to which individuals exhibit a post-infectious IgG antibody response to SARS-CoV-2 is highly variable - many persons have no antibodies detected in the peripheral circulation within weeks to months following resolution of symptoms. We hypothesize that: (H1) the natural history of response to SARS-CoV-2 exposure is marked by discernible patterns of susceptibility vs resistance that vary by demographic, clinical, and host-environment factors; and, (H2) divergent clinical trajectories are driven by underlying inter-individual differences in the complex immune- inflammatory response to SARS-CoV-2 exposure. Based on early observations and emerging data, we anticipate four potential clinical trajectories among exposed individuals: (i) those with exposure, but apparently no infection; (ii) infection with minimal to no symptoms, then persistent immunity; (ii) infection with symptoms, recovery, persistent immunity; and, (iv) infection, recovery, re-infection. To test these hypotheses, we propose to leverage our existing CORALE study (n=10,370), a prospective longitudinal cohort study at a major metropolitan healthcare system in Southern California. Our catchment area includes large numbers of Hispanic/LatinX, Black, and Asian individuals across the age range, representing high-risk and understudied populations; in turn, our health system is one of the nation's highest volume centers for treating COVID-19 patients. Our specific aims are to: (1) identify distinct trajectories and determinants of susceptibility and immunity to SARS-CoV-2; and (2) identify distinct immune-inflammatory profiles (including bioactive lipid eicosanoids, acute phase proteins, cytokines, and their derivatives) associated with susceptibility and immunity to SARS-CoV-2. We will use both baseline measures and perform serial SARS-CoV-2 serologic measures (IgG + IgM) to longitudinally map serologic response with clinical and functional measures and define specific trajectories of susceptibility vs resistance (i.e. variations in degree of vulnerability to infection and illness, rate of recovery, and ability to maintain durable clinical immunity to re-infection or co-infection by other viral illnesses such as influenza). Lastly, we will examine heterogeneity in trajectories by sex, age, race/ethnicity, socioeconomic status, and host-environment modifiers (e.g. smoking, diet, and other lifestyle/behavioral factors). This CORALE-SeroNet Project 1 will identify the clinical and molecular profiles that signal robust immune reconstitution and functional recovery following SARS-CoV-2 exposure in multiple diverse populations including understudied minorities.