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Comorbid illnesses are associated with altered adaptive immune responses to SARS-CoV-2

Yu, KK;Fischinger, S;Smith, MT;Atyeo, C;Cizmeci, D;Wolf, CR;Layton, ED;Logue, JK;Aguilar, MS;Shuey, K;Loos, C;Yu, J;Franko, NM;Choi, RY;Wald, A;Barouch, DH;Koelle, DM;Lauffenburger, D;Chu, HY;Alter, G;Seshadri, C;

Comorbid medical illnesses, such as obesity and diabetes, are associated with more severe COVID-19, hospitalization, and death. However, the role of the immune system in mediating these clinical outcomes has not been determined. We used multi-parameter flow cytometry and systems serology to comprehensively profile the functions of T cells and antibodies targeting spike, nucleocapsid, and envelope proteins in a convalescent cohort of COVID-19 subjects who were either hospitalized (n=20) or not hospitalized (n=40). To avoid confounding, subjects were matched by age, sex, ethnicity, and date of symptom onset. Surprisingly, we found that the magnitude and functional breadth of virus-specific CD4 T cell and antibody responses were consistently higher among hospitalized subjects, particularly those with medical comorbidities. However, an integrated analysis identified more coordination between polyfunctional CD4 T-cells and antibodies targeting the S1 domain of spike among subjects that were not hospitalized. These data reveal a functionally diverse and coordinated response between T cells and antibodies targeting SARS-CoV-2, which is reduced in the presence of comorbid illnesses that are known risk factors for severe COVID-19.