Combinatorial analysis reveals highly coordinated early-stage immune reactions that predict later antiviral immunity in mild COVID-19 patients

While immunopathology has been widely studied in patients with severe COVID-19, immune responses in non-hospitalized patients have remained largely elusive. We systematically analyze 484 peripheral cellular or soluble immune features in a longitudinal cohort of 63 mild and 15 hospitalized patients versus 14 asymptomatic and 26 household controls. We observe a transient increase of IP10/CXCL10 and interferon-β levels, coordinated responses of dominant SARS-CoV-2-specific CD4 and fewer CD8 T cells, and various antigen-presenting and antibody-secreting cells in mild patients within 3 days of PCR diagnosis. The frequency of key innate immune cells and their functional marker expression are impaired in hospitalized patients at day 1 of inclusion. T cell and dendritic cell responses at day 1 are highly predictive for SARS-CoV-2-specific antibody responses after 3 weeks in mild but not hospitalized patients. Our systematic analysis reveals a combinatorial picture and trajectory of various arms of the highly coordinated early-stage immune responses in mild COVID-19 patients. [Display omitted] •Highly coordinated early-stage immune responses are confined to mild patients•Early immune reactions can predict Ab responses 3 weeks later in mild patients•Transient early surge of IFN-β and IP10 correlates with viral load in mild patients•Dominant virus-specific CD4 T cells appear in both mild and hospitalized patients In a parallel, longitudinal, prospective cohort based on a general population, using a systems-immunology analysis approach, Capelle et al. provide a comprehensive resource of multi-layered early immunological responses in mild COVID-19 patients. They reveal that a combination of highly coordinated early-stage immune responses is unique to mild patients.