Integrated immune dynamics define correlates of COVID-19 severity and antibody responses

Koutsakos, Marios; Rowntree, Louise C.; Hensen, Luca; Chua, Brendon Y.; van de Sandt, Carolien E.; Habel, Jennifer R.; Zhang, Wuji; Jia, Xiaoxiao; Kedzierski, Lukasz; Ashhurst, Thomas M.; Putri, Givanna H.; Marsh-Wakefield, Felix; Read, Mark N.; Edwards, Davis N.; Clemens, E Bridie; Wong, Chinn Yi; Mordant, Francesca L.; Juno, Jennifer A.; Amanat, Fatima; Audsley, Jennifer; Holmes, Natasha E.; Gordon, Claire L.; Smibert, Olivia C.; Trubiano, Jason A.; Hughes, Carly M.; Catton, Mike; Denholm, Justin T.; Tong, Steven YC.; Doolan, Denise L.; Kotsimbos, Tom C.; Jackson, David C.; Krammer, Florian; Godfrey, Dale I.; Chung, Amy W.; King, Nicholas JC.; Lewin, Sharon R.; Wheatley, Adam K.; Kent, Stephen J.; Subbarao, Kanta; McMahon, James; Thevarajan, Irani; Nguyen, Thi HO.; Cheng, Allen C.; Kedzierska, Katherine

SARS-CoV-2 causes a spectrum of COVID-19 disease, the immunological basis of which remains ill-defined. We analysed 85 SARS-CoV-2-infected individuals at acute and/or convalescent timepoints, up to 102 days post-symptom onset, quantifying 184 immunological parameters. Acute COVID-19 presented with high levels of IL-6, IL-18 and IL-10 and broad activation marked by upregulation of CD38 on innate and adaptive lymphocytes and myeloid cells. Importantly, activated CXCR3+cTFH1 cells in acute COVID-19 significantly correlate with and predict antibody levels and their avidity at convalescence as well as acute neutralisation activity. Strikingly, intensive care unit (ICU) patients with severe COVID-19 display higher levels of soluble IL-6, IL-6R, IL-18, and hyperactivation of innate, adaptive and myeloid compartments than patients with moderate disease. Our analyses provide a comprehensive map of longitudinal immunological responses in COVID-19 patients and integrate key cellular pathways of complex immune networks underpinning severe COVID-19, providing important insights into potential biomarkers and immunotherapies.