THE SEARCH FOR COVID-19 PREVENTION AND CURE: ADDRESSING THE CRITICAL ROLE OF INNATE/ADAPTIVE IMMUNITY BY INTEGRATING NOVEL INFORMATICS, TRANSLATIONAL TECHNOLOGIES, AND ONGOING CLINICAL TRIAL RESEARCH

Individual CTSA hubs are leading the national clinical and translational research efforts in developing newapproaches to address the COVID-19 pandemic. This crucial role was natural. Long before the current crisis,CTSA hubs were committed to translation, building multidisciplinary teams of investigators and communitypartners, overcoming regulatory burdens, ensuring quality in clinical and human research, developingtransformative informatics, and disruptive technologies for diagnostics and therapeutics. In this proposal, webuild on our center's active participation in meaningful clinical trials (e.g., the NIH Remdesivir RCT), the earlycreation of a biospecimen repository from COVID-19 patients, institutional commitment and fundraising that ledto a $3.5 million pilot fund distribution, a robust and accessible clinical database repository, and the ongoingwork of an NCATS-supported CTSA Collaboration Innovation Award (a coalition of the J. Craig Venter Institute,UCSD, UCI, and Stanford) focused on artificial intelligence approaches for the analysis of flow cytometrydata. Using the emerging informatics framework of supervised generalized canonical correlation forintegrative data analysis, we will link clinical data from COVID-19 patients enrolled in a variety of trials andat various stages of disease with innovative in vitro evaluation of innate and adaptive immunity, an areastill poorly understood in SARS-CoV-2 pathology, obtained from patient biospecimens to obtain mechanisticinsights of COVID-19 pathogenesis at a systems level. Innate and adaptive immunity are particularlyrelevant to COVID-19 disease pathogenesis because they play key, but distinct, roles at all phases of theillness (initial tissue-virus interaction; systemic responses; the cell-mediated cytokine storm leading to multi-organ failure and death, likely long after levels of viremia have fallen; and, ultimately, protective immunity). Thecurrent CCIA novel flow cytometry informatics research permits elucidation of dynamic cellular immuneresponses related to the COVID-19 pandemic that were heretofore unobservable. Using Hi-DAFi for masscytometry analysis, validated informatics pipelines for single cell transcriptomics analysis, and cutting-edgestatistical data integration and machine learning strategies tied back to the available clinical data we will beable to discover novel associations between cellular biomarkers and disease state, a particular therapy, anddisease mediating factors such as age, health disparities, and the presence of other diseases or conditions likeobesity. This information will aid in critical efforts to target new therapies and possibly identify idiosyncraticindividual physiologic variables that render certain patients who seem to have no known comorbidities morevulnerable to severe COVID-19 disease. Finally, the robust connection between the UCI hub and both regionaland national networks (e.g., BRAID, the coalition of the 5 UC CTSAs, and NCATS Trial Innovation Network)will provide an unprecedented opportunity to rapidly disseminate clinically relevant discoveries and engage thetalent and insight of the many clinicians and scientists working tirelessly to end this pandemic.