Antigen-specific T-cell responses to SARS-CoV-2 vaccination after hematopoietic cell transplant or CAR T-cell therapy

Abstract

The optimal timing of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination after cellular therapies remains uncertain. In a previous prospective multicenter cohort (n = 466), we found no differences in humoral or SARS-CoV-2-specific T-cell receptor (TCR) responses between patients vaccinated early (<4 months) vs later (4-12 months) after allogeneic hematopoietic cell transplant (allo-HCT), autologous HCT (auto-HCT), or chimeric antigen receptor T-cell (CAR-T) therapy. In this substudy, we evaluated functional T-cell responses in 68 patients (allo-HCT, n = 28; auto-HCT, n = 22; CAR-T, n = 18) that were clinically and immunophenotypically similar to that of the overall cohort. Antigen-specific CD4+ and CD8+ T-cell responses to SARS-CoV-2 messenger RNA (mRNA) vaccination were assessed by spectral flow cytometry. Functional responses were correlated with baseline immune reconstitution parameters, antibody responses, and SARS-CoV-2-specific TCR repertoire metrics. Vaccination induced significant increases in antigen-specific interferon gamma and tumor necrosis factor α production by both CD4+ and CD8+ T cells across all cellular therapy groups. Responses were primarily driven by CD4+ central memory and cytotoxic CD8+ T-cell subsets. Functional T-cell responses correlated with baseline CD19+ B-cell counts (P = .002) and postvaccination antibody responses (P< .01) but not with SARS-CoV-2-specific TCR breadth or depth. Notably, functional T-cell responses were detectable even in patients with low B-cell counts or absent antibody responses. We conclude that mRNA SARS-CoV-2 vaccination elicits functional, T helper 1-skewed T-cell responses after allo-HCT, auto-HCT, and CAR-T therapy. Initiation of SARS-CoV-2 vaccination early after cellular therapy (<4 months) was not associated with impaired functional T-cell responses.