Magnitude of venous or capillary blood-derived SARS-CoV-2-specific T cell response determines COVID-19 immunity

Abstract

T cells specific for SARS-CoV-2 are thought to protect against infection and development of COVID-19, but direct evidence for this is lacking. Here, we associated whole-blood-based measurement of SARS-CoV-2-specific interferon-γ-positive T cell responses with positive COVID-19 diagnostic (PCR and/or lateral flow) test results up to 6 months post-blood sampling. Amongst 148 participants donating venous blood samples, SARS-CoV-2-specific T cell response magnitude is significantly greater in those who remain protected versus those who become infected (P < 0.0001); relatively low magnitude T cell response results in a 43.2% risk of infection, whereas high magnitude reduces this risk to 5.4%. These findings are recapitulated in a further 299 participants testing a scalable capillary blood-based assay that could facilitate the acquisition of population-scale T cell immunity data (14.9% and 4.4%, respectively). Hence, measurement of SARS-CoV-2-specific T cells can prognosticate infection risk and should be assessed when monitoring individual and population immunity status.

Fig. 1. Magnitude of anti-SARS-CoV-2 T cell and IgG responses measured in venous blood samples.

a SARS-CoV-2-specific IFN-γ⁺ T cell responses were measured using the venous whole blood assay and sub-divided based on participant vaccination and prior SARS-CoV-2 (PCR and/or lateral flow test confirmed) infection status. ‘Vac + /Inf + ’ n = 60 (green), ‘Vac + /Inf-’ n = 82 (blue), ‘Vac-/Inf + ’ n = 4 (yellow), ‘Vac-/Inf-’ n = 1 (not plotted). SARS-CoV-2-specific IgG-binding responses targeting nucleocapsid (‘N’) (b; ****P < 0.0001, **P = 0.0016), spike receptor binding domain (‘RBD’) (c; **P = 0.0022, *P < 0.015), spike subunit 1 (‘S1’) (d; ***P = 0.0005, *(Vac + /Inf+ vs. Vac + /Inf-) P = 0.022, *(Vac-/Inf+ vs. Vac + /Inf-) P = 0.012) and spike subunit 2 (‘S2’) (e) were measured using the venous whole blood assay and sub-divided based on participant vaccination and prior SARS-CoV-2 (PCR and/or lateral flow test confirmed) infection status. ‘Vac + /Inf + ’ n = 60 (green), ‘Vac + /Inf-’ n = 71-82 (blue), ‘Vac-/Inf + ’ n = 4 (yellow). Comparisons used Kruskal-Wallis tests with correction for multiple comparisons using Dunn’s tests. Data are presented as box plots (centre line at the median, upper bound at 75th percentile, lower bound at 25th percentile) with whiskers at minimum and maximum values. Each dot represents one donor. Source data are provided as a Source Data file.

Fig. 2. Magnitude of anti-SARS-CoV-2 adaptive immune responses measured in venous blood samples up to six months preceding a positive COVID-19 test.

Venous blood samples obtained from healthy donors (n = 148) were assessed for the magnitude of SARS-CoV-2-specific IFN-γ⁺ T cell responses (a; ****P < 0.0001) and SARS-CoV-2-specific IgG-binding responses targeting spike receptor binding domain (‘RBD’) (b), spike subunit 1 (‘S1’) (c), spike subunit 2 (‘S2’) (d) and nucleocapsid (‘N’) (e; **P = 0.0084). Participants self-reporting a COVID-19 positive test (PCR and/or lateral flow test) are highlighted; all cases of infection occurred within 6 months of blood draw. Comparisons used two-sided Mann–Whitney tests. Data are presented as box plots (centre line at the median, upper bound at 75th percentile, lower bound at 25th percentile) with whiskers at minimum and maximum values. Each dot represents one donor. ns not significant. f Heat map demonstrating Spearman’s rank correlations between specified dataset variables. Comparisons that were not statistically significant were excluded from the matrix and are represented by empty boxes. Source data are provided as a Source Data file.

Fig. 3. Magnitude of anti-SARS-CoV-2 T cell and IgG responses measured in capillary blood samples.

a SARS-CoV-2-specific IFN-γ⁺ T cell responses were measured using the capillary whole blood assay and sub-divided based on participant vaccination and prior SARS-CoV-2 (PCR and/or lateral flow test confirmed) infection status. ‘Vac + /Inf + ’ n = 42 (green), ‘Vac + /Inf-’ n = 158 (blue), ‘Vac-/Inf + ’ n = 33 (yellow), ‘Vac-/Inf-’ n = 37 (grey). ****P < 0.0001, ***P = 0.0001, *(Vac + /Inf- vs. Vac-/Inf-) P = 0.045, *(Vac-/Inf+ vs. Vac-/Inf-) P = 0.014. SARS-CoV-2-specific IgG-binding responses targeting spike receptor binding domain (‘RBD’) (b; ****P < 0.0001, ns: not significant), spike subunit 1 (‘S1’) (c; ****P < 0.0001, ns: not significant), spike subunit 2 (‘S2’) (d; ****P < 0.0001, ***P = 0.0005, *P = 0.016) and nucleocapsid (‘N’) (e; ****P < 0.0001, ns not significant) were measured using the venous whole blood assay and sub-divided based on participant vaccination and prior SARS-CoV-2 (PCR and/or lateral flow test confirmed) infection status. ‘Vac + /Inf + ’ n = 46 (green), ‘Vac + /Inf-’ n = 182 (blue), ‘Vac-/Inf + ’ n = 34 (yellow), ‘Vac-/Inf-’ n = 37 (grey). Comparisons used Kruskal-Wallis tests with correction for multiple comparisons using Dunn’s tests. Data are presented as box plots (centre line at the median, upper bound at 75th percentile, lower bound at 25th percentile) with whiskers at minimum and maximum values. Each dot represents one donor. Source data are provided as a Source Data file.

Fig. 4. Magnitude of anti-SARS-CoV-2 adaptive immune responses measured in capillary blood samples up to 3 months preceding a positive COVID-19 test.

Capillary blood samples obtained from study participants (n = 299) were assessed for the magnitude of SARS-CoV-2-specific IFN-γ⁺ T cell responses (a; *P = 0.034) and SARS-CoV-2-specific IgG-binding responses targeting spike receptor binding domain (‘RBD’) (b), spike subunit 1 (‘S1’) (c), spike subunit 2 (‘S2’) (d) and nucleocapsid (‘N’) (e). Participants self-reporting a COVID-19 positive test (PCR and/or lateral flow test) are highlighted; all cases of infection occurred within 3 months of blood draw. Comparisons used two-sided Mann–Whitney tests. Data are presented as box plots (centre line at the median, upper bound at 75th percentile, lower bound at 25th percentile) with whiskers at minimum and maximum values. Each dot represents one donor. ns not significant. f Heat map demonstrating Spearman’s rank correlations between specified dataset variables. Comparisons that were not statistically significant were excluded from the matrix and are represented by empty boxes. Source data are provided as a Source Data file.