Introduction: Kidney transplant recipients (KTRs) continue to face increased risk for developing severe COVID-19 due to weakened immune responses resulting from immunosuppressive treatments. Despite vaccination efforts, poor vaccine efficacy persists among this population. To mitigate this risk, repeated vaccinations are recommended. However, evolving variants pose challenges by evading neutralizing antibodies. Since T-cells retain the capacity to recognize diverse SARS-CoV-2 variants, understanding the role of different T-cell phenotypes post-repeated vaccination for improved protection in this vulnerable population is crucial. Our objective was to examine the effect of a third COVID-19 vaccination on T-cell responses in KTRs, unraveling the association between T-cell phenotype diversity and SARS-CoV-2 antibody responses.
Methods: In this study, eighty-eight KTRs with poor serological responses to two primary mRNA-1273 vaccinations were randomly assigned to different booster strategies: a double dose of mRNA-1273 (n=27), a heterologous Ad26.COV2.S vaccination (n=30), or a single dose of mRNA-1273 (n=31). Whole blood was collected pre- and 28 days post-vaccination, then stimulated with overlapping peptides of the SARS-CoV-2 spike protein. T-cell cytokines (IL-2, -4, -5, -9, -10, -13, -17A, -17F, -22, IFN-γ, and TNF-α) were quantified in plasma using a multiplex bead assay.
Results: After the third vaccination, a significant increase in antibody levels was observed among the majority of KTRs, despite their initial low responses. Examination of cytokine profiles revealed variance in IFN-γ, IL-2, IL-5, and IL-13  production between KTRs with high or low antibody levels. Interestingly, the production of IL-2 and IL-5 by SARS-CoV-2-specific T-cells correlated (r=0.50, p<0.001 and r=0.48, p<0.001, respectively) with antibody levels, whereas the correlation with IFN-γ (a commonly used marker for SARS-CoV-2 specific T-cells) was weaker (r=0.23, p<0.01). Furthermore, it was noted that IFN-γ production by SARS-CoV-2 specific T-cells was less prevalent among KTRs compared to the production of IL-2 and IL-5.
Conclusion: This study provides insight on the specific T-cell responses to SARS-CoV-2 following a third vaccination in KTRs who initially showed poor serological responses. Furthermore, it underscores the limitations of relying solely on IFN-γ as a biomarker for assessing SARS-CoV-2-specific T-cell responses in this group, emphasizing the importance of inducing balanced Th1-Th2 responses. These findings suggest that a more comprehensive examination of T-cell phenotypes could offer a promising approach for evaluating T-cell responses to vaccines in vulnerable populations such as KTRs.