(A) Intracellular cytokine staining was used to profile the functions of CD4⁺ T cells specific for the S1 and S2 domains of spike, nucleocapsid (N), and envelope small membrane protein (E). Data were analyzed using COMPASS, and results are displayed as a probability heatmap in which the rows represent study subjects and the columns represent CD4⁺ T cell functional subsets. The depth of shading within the heatmap represents the probability of detecting a response above background. In the column legend, white indicates absence and black/gray indicates presence of a function. (B) Background subtracted magnitudes of CD4⁺ T cell responses stratified by the presence of IFN-γ. (C) Representative bivariate flow cytometry plots showing the expression of IFN-γ and CD40L following stimulation. (D) Cells expressing any of the functional profiles identified by COMPASS were aggregated across all subjects prior to performing dimensionality reduction with UMAP. Plots are stratified and colored according to hospitalization status, stimulation, effector function, memory markers (naive, CD45RA⁺CCR7⁺; central memory [TCM], CD45RA^–CCR7⁺; effector memory [TEM], CD45RA^–CCR7^–; and effector memory RA [TEMRA], CD45RA⁺CCR7^–), and activation markers (HLA-DR, CD38). Polyfunctionality (PolyF) was calculated as the number of cytokines gated positive for each cell. (E) Magnitudes of CD4⁺ T cells expressing a CD40L⁺IL-2⁺TNF⁺ functional profile in the presence or absence of IFN-γ are compared across stimulations. (F) Magnitudes of CD4⁺ T cells expressing CD107a in the absence of all other functions are compared across stimulations. Wilcoxon signed-rank tests were used to compare frequencies between groups in B and E. E reports Bonferroni-corrected P values, but B is unadjusted. Median, 25th, and 75th quartiles are indicated for violin plots. If not shown, P values were not significant. n = 60 in all panels.