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Host immune responses play central roles in controlling SARS-CoV2 infection, yet remain incompletely characterized and understood. Here, we present a comprehensive immune response map spanning 454 proteins and 847 metabolites in plasma integrated with single-cell multi-omic assays of PBMCs in which whole transcriptome, 192 surface proteins, and T and B cell receptor sequence were co-analyzed within the context of clinical measures from 50 COVID19 patient samples. Our study reveals novel cellular subpopulations, such as proliferative exhausted CD8+ and CD4+ T cells, and cytotoxic CD4+ T cells, that may be features of severe COVID-19 infection. We condensed over 1 million immune features into a single immune response axis that independently aligns with many clinical features and is also strongly associated with disease severity. Our study represents an important resource towards understanding the heterogeneous immune responses of COVID-19 patients and may provide key information for informing therapeutic development. ### Competing Interest Statement J.R.H. is founder and board member of Isoplexis and PACT Pharma. M.M.D. is the board member of PACT Pharma. J.A.B. is a member of the Scientific Advisory Boards of Arcus, Celsius, and VIR. JAB is a member of the Board of Directors of Rheos and Provention. JAB has recently joined Sonoma Biotherapeutics as President and CEO. Sonoma Biotherapeutics is involved in developing novel Treg-based cell therapies for the treatment of autoimmune diseases. The remaining authors declare no competing interests.

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