Project 1: Systems Analyses of Heterologous Immunity During CMV Infection in Renal Transplantation

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SARS-CoV-2 virus infection and associated COVID-19 disease has caused unparalleled global morbidity and mortality in previously healthy patients, with over 4 million cases and 150,000 deaths in the US alone. Older patients, who experience immune dysfunction associated with aging, and patients with underlying health issues, such as chronic kidney disease, have been inequitably burdened by COVID-19. Understanding correlates of protection against SARS-CoV-2 infection and why these immunocompromised patients apparently possess deficiencies in generating these protective immune responses is critical to developing clinical practices for these at-risk populations. To address this fundamental knowledge gap, this study will characterize the natural immune response to SARS-CoV-2 virus infection in immunocompromised patients and determine whether immunity is long-lasting. Specifically, we will evaluate the quantity and quality of antibodies against SARS-CoV-2 and their relationship to frequency and functionality of SARS-CoV-2-specific T cells, therefore generating a complete picture of the adaptive immune response to SARS-CoV-2 in immunocompromised patients. To achieve our goal, we have utilized four kidney transplant centers within the University of California to establish a cohort of 2500 patients with end-stage renal disease (ESRD) awaiting transplant and 2000 renal transplant recipients with banked pre- and post-COVID-19 pandemic sera across a highly racially and ethnically diverse population, of which 40% are from minority populations that have been inequitably burdened by COVID-19. We will screen for exposure to SARS-CoV-2 in the complete cohort of 4500 patients, enrolling 100 ESRD and 76 renal transplant recipients with evidence of SARS-CoV-2-specific antibodies, based on a recent population seroprevalence estimate of 4% in Los Angeles. We will additionally recruit matched patients without evidence of SARS-CoV-2-specific antibodies. Antibody titer, isotype, subclass, avidity, infection neutralization and ability to interface with cell-mediated immunity will be determined at baseline with longitudinal follow-up 3-6 month and 9- 12 months later to assess longevity of humoral immune responses to SARS-CoV-2. Similarly, we will delineate the frequency, phenotype and longevity of SARS-CoV-2-specific cellular immune responses. This study will generate an extensive repository of clinical phenotypes, outcomes, and high-dimensional blood and urine profiling data on longitudinal samples of patients with and without exposure to SARS-CoV-2 in the California transplant population, providing an invaluable resource for the research community in understanding immunity to SARS-CoV-2. Utilizing state-of-the-art biostatistics and computational approaches, we will integrate high-dimensional data of humoral and cellular immune responses to develop models of combined adaptive immune profiles following SARS-CoV-2 exposure and assess their longevity and likelihood of protecting upon re-exposure.