Th(1)-dominant cytokine responses in kidney patients after COVID-19 vaccination are associated with poor humoral responses.

Cytokines are regulators of the immune response against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). However, the contribution of cytokine-secreting CD4(+) and CD8(+) memory T cells to the SARS-CoV-2-specific humoral immune response in immunocompromised kidney patients is unknown. Here, we profiled 12 cytokines after stimulation of whole blood obtained 28 days post second 100 μg mRNA-1273 vaccination with peptides covering the SARS-CoV-2 spike (S)-protein from patients with chronic kidney disease (CKD) stage 4/5, on dialysis, kidney transplant recipients (KTR), and healthy controls. Unsupervised hierarchical clustering analysis revealed two distinct vaccine-induced cytokine profiles. The first profile was characterized by high levels of T-helper (Th)(1) (IL-2, TNF-α, and IFN-γ) and Th(2) (IL-4, IL-5, IL-13) cytokines, and low levels of Th(17) (IL-17A, IL-22) and Th(9) (IL-9) cytokines. This cluster was dominated by patients with CKD, on dialysis, and healthy controls. In contrast, the second cytokine profile contained predominantly KTRs producing mainly Th(1) cytokines upon re-stimulation, with lower levels or absence of Th(2), Th(17), and Th(9) cytokines. Multivariate analyses indicated that a balanced memory T cell response with the production of Th(1) and Th(2) cytokines was associated with high levels of S1-specific binding and neutralizing antibodies mainly at 6 months after second vaccination. In conclusion, seroconversion is associated with the balanced production of cytokines by memory T cells. This emphasizes the importance of measuring multiple T cell cytokines to understand their influence on seroconversion and potentially gain more information about the protection induced by vaccine-induced memory T cells.