doi: 10.3324/haematol.2024.287136.
Epub 2025 May 29.
T-cell and antibody responses in immunocompromised patients with hematologic malignancies indicate strong potential of SARS-CoV-2 mRNA vaccines
Affiliations
- PMID: 40438989
- PMCID: PMC12580724
- DOI: 10.3324/haematol.2024.287136
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T-cell and antibody responses in immunocompromised patients with hematologic malignancies indicate strong potential of SARS-CoV-2 mRNA vaccines
Haematologica.
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No abstract available
Figures
Vaccination-induced spike-specific antibody and T-cell responses in patients with hematologic malignancies. Before and 4 weeks after each mRNA-1273 vaccination, serum and peripheral blood mononucelar cells (PBMC) were collected to measure antibodies and T cells. (A) Spike protein S1 subunit (S1) immunoglobulin (Ig)G antibody concentrations after 2 SARS-CoV-2 mRNA vaccinations, categorized as no seroconversion (red; median S1 IgG <10 binding antibody units [BAU]/mL), low concentration (orange; median S1 IgG 10-300 BAU/mL), or adequate concentration (green; median S1 IgG >300 BAU/mL). Dotted line indicates seroconversion threshold. S1 IgG >300 BAU/mL was considered an adequate antibody response against the ancestral SARS-CoV-2, since this IgG concentration corresponded with a 50% plaque reduction neutralization titer of 40 or higher in 2 independent prospective Dutch mRNA-1273 vaccination cohorts. Concentrations of S1 and N IgG were quantified in BAU/mL according to the World Health Organization International Standard for COVID-19 serological tests. (B) Number of B cells/mL blood at start of vaccination (baseline). Dotted lines indicate range in healthy individuals (HI) (100-500 cells/mL blood). Squares indicate categorization of the cohorts based on the median. Cohorts with a median value below the arbitrary threshold of 10 cells/mL are depicted as red, with a median between 10 and 100 are depicted as orange, and with a median above 100 as green. (C, D) Frequency of spike-specific CD4+ or CD8+ T cells after two SARS-CoV-2 mRNA vaccinations as determined by activation-induced marker (AIM) assay and, for CD8+ T cells, in combination with peptide-HLA tetramer staining. For the AIM assay, 2 million thawed PBMC were incubated with 15-mer spike peptides (SB peptide, France), dimethyl sulfoxide (DMSO)-negative control, or a Cytomegalovirus, Epstein-Barr virus, Influenza (Flu) and extra (CEFX) peptide pool (JPT). After 1 hour, brefeldin A was added. All time points of 1 patient were measured simultaneously to minimize technical variance within 1 patient. Patients were measured and analyzed in random order across cohorts to minimize technical variance and bias between cohorts. Fifteen hours after adding brefeldin A, cells were stained for viability, fixated, permeabilized and incubated with antibodies directed against CD3, CD4, CD8, CD154, CD137, CD69, IFN-g, TNF-a, IL-2, IL-4, IL-17, PD-1, FOXP3 and CXCR5. In parallel, PBMC were incubated with a viability dye, peptide-HLA tetramers and antibodies directed against CD4, CD8, CCR7 and CD45RA. Dotted lines indicate response positivity threshold (0.05% for CD4+, 0.025% for CD8+). (E, F) Frequency of spike-specific CD4+ (E) or CD8+ (F) T cells that produce IFN-g, TNF-a and/or IL-2. Th1 cytokine-positive frequency was calculated by subtracting the frequency of cells that do not produce any of these cytokines from 100%. For all panels, grey horizontal area corresponds to interquartile range in HI. T-cell frequencies from each cohort are compared to those in HI by Mann-Whitney U tests and significance corrected for multiple testing (times 16) is shown (not significant P>0.05; *P≤0.05; **P≤0.01; ***P≤0.001; ****P≤0.0001). Squares indicate categorization of the T-cell responses based on P value prior to and after correction for multiple testing (green when not significantly lower prior to correction; orange when significantly lower before, but not after correction; red when significantly lower after correction). aCD20: during anti-CD20 therapy; >aCD20: within 12 months after anti-CD20 therapy; HSCT: hematopoietic stem cell transplantation; BEAM: BEAM-autologous HSCT within 12 months; CAR T: CD19 chimeric antigen receptor T-cell therapy; CLL: chronic lymphocytic leukemia; W&W: watch and wait; BTKi: Bruton’s tyrosine kinase inhibitor ibrutinib; MM: multiple myeloma; VTD: bortezomib-thalidomide-dexamethasone induction therapy; aCD38: daratumumab; ImiD: immunomodulatory drugs; HDM: high-dose melphalan and autologous HSCT within 9 months; MDS: myelodysplastic syndrome; AML: acute myeloid leukemia and high-risk MDS; chemo: high-dose chemotherapy; HMA: hypomethylating agents; MPN: myeloproliferative neoplasms; JAK2i: Janus 2 kinase inhibitor ruxolitinib; CML: chronic myeloid leukemia; TKI: tyrosine kinase inhibitors; alloHSCT: allogeneic hematopoietic stem cell transplantation; cGVHD: chronic graft-versus-host disease.
Baseline parameters, number of spike-specific T cells, and integrated analysis of cellular and humoral immune responses. (A) Categorization of spike-spike specific CD4+ or CD8+ T cell frequencies as shown in Figure 1. Spike protein S1 subunit (S1) immunoglobulin (Ig)G antibody concentrations after 2 SARS-CoV-2 mRNA vaccinations, categorized as no seroconversion (red; median S1 IgG <10 binding antibody units [BAU]/mL), low concentration (orange; median S1 IgG 10-300 BAU/mL), or adequate concentration (green; median S1 IgG >300 BAU/mL). (B) CD4+ or CD8+ T-cell numbers directly measured in blood as cells/mL. Absolute numbers of lymphocyte subsets were determined using fresh whole EDTA blood with Multitest 6-color reagents (BD Biosciences, San Jose, CA, USA) according to the manufacturer’s instructions. The dotted lines indicate the clinically-accepted normal ranges in healthy individuals (HI). (C) Frequency of naïve (CCR7+CD45RA+) CD4+ or CD8+ T cells. Grey horizontal area corresponds to interquartile range in HI. (D) Number of spike-specific CD4+ or CD8+ T cells in peripheral blood, calculated by multiplying the percentage of spike-specific T cells by the number of T cells in peripheral blood. (E) Categorization of mRNA vaccine-induced B- and T-cell immune responses, and number of circulating B cells at start of vaccination per cohort. Categorization was based on median (S1 IgG), clinically accepted threshold (B cells), or statistics (T-cell responses). T-cell responses are categorized based on significance before and after correction for multiple testing (green when not significantly lower before correction; orange when significantly lower before, but not after correction; red when significantly lower after correction). Categorization of cytokine-producing spike-specific CD8+ T-cell frequencies is not depicted due to limited availability of data points. (F) Summary heatmap of the data gathered from 6 variables of all cohorts, generated using RStudio (R-4.3.0, packages: circlize-0.4.15, ComplexHeatmap-2.15.4). Each vertical line represents the same individual. However, S1 IgG concentrations were obtained from an independent HI cohort (blue box), therefore, the vertical lines of the S1 IgG in HI do not represent the same vertical lines as the HI cohort of the T-cell data. Values are color-coded by relative abundance within each variable. The minimum value (red) was set to zero, the maximum (dark green) to the highest measured value, and the median (light green) to the median value in healthy individuals. B cells were not measured in HI and therefore the light-green median is set to the clinically-accepted minimal normal value of 100 cells/mL. Unavailable data are shown as white-colored bars. Cytokine-postive frequency of S1 CD4/8+ indicates frequency of spike-specific CD4/8+ T cells that produce IFN-g, TNF-a and/or IL-2. aCD20: during anti-CD20 therapy; >αCD20: within 12 months after anti-CD20 therapy; HSCT: hematopoietic stem cell transplantation; BEAM: BEAM-autologous HSCT within 12 months; CAR T: CD19 chimeric antigen receptor T-cell therapy; CLL: chronic lymphocytic leukemia; W&W: watch and wait; BTKi: Bruton’s tyrosine kinase inhibitor ibrutinib; MM: multiple myeloma; VTD: bortezomib-thalidomide-dexamethasone induction therapy; aCD38: daratumumab; ImiD: immunomodulatory drugs; HDM: high-dose melphalan and autologous HSCT within 9 months; MDS: myelodysplastic syndrome; AML: acute myeloid leukemia and high-risk MDS; chemo: high-dose chemotherapy; HMA: hypomethylating agents; MPN: myeloproliferative neoplasms; JAK2i: Janus 2 kinase inhibitor ruxolitinib; CML: chronic myeloid leukemia; TKI: tyrosine kinase inhibitors; alloHSCT: allogeneic hematopoietic cell transplantation; cGVHD: chronic graft-versus-host disease.
References
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- Zonozi R, Walters LC, Shulkin A, et al. T cell responses to SARS-CoV-2 infection and vaccination are elevated in B cell deficiency and reduce risk of severe COVID-19. Sci Transl Med. 2023;15(724):eadh4529. - PubMed
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