- Moderbacher, Carolyn Rydyznski;
- Ramirez, Sydney I;
- Dan, Jennifer M;
- Grifoni, Alba;
- Hastie, Kathryn M;
- Weiskopf, Daniela;
- Belanger, Simon;
- Abbott, Robert K;
- Kim, Christina;
- Choi, Jinyong;
- Kato, Yu;
- Crotty, Eleanor G;
- Kim, Cheryl;
- Rawlings, Stephen A;
- Mateus, Jose;
- Tse, Long Ping Victor;
- Frazier, April;
- Baric, Ralph;
- Peters, Bjoern;
- Greenbaum, Jason;
- Saphire, Erica Ollmann;
- Smith, Davey M;
- Sette, Alessandro;
- Crotty, Shane
Limited knowledge is available on the relationship between antigen-specific immune responses and COVID-19 disease severity. We completed a combined examination of all three branches of adaptive immunity at the level of SARS-CoV-2-specific CD4+ and CD8+ T cell and neutralizing antibody responses in acute and convalescent subjects. SARS-CoV-2-specific CD4+ and CD8+ T cells were each associated with milder disease. Coordinated SARS-CoV-2-specific adaptive immune responses were associated with milder disease, suggesting roles for both CD4+ and CD8+ T cells in protective immunity in COVID-19. Notably, coordination of SARS-CoV-2 antigen-specific responses was disrupted in individuals ≥ 65 years old. Scarcity of naive T cells was also associated with aging and poor disease outcomes. A parsimonious explanation is that coordinated CD4+ T cell, CD8+ T cell, and antibody responses are protective, but uncoordinated responses frequently fail to control disease, with a connection between aging and impaired adaptive immune responses to SARS-CoV-2.