Background: Kidney transplant recipients (KTRs) demonstrate a suboptimal response to SARS-CoV-2 vaccination due to chronic immunosuppression. An additional vaccine dose successfully elicits an antibody response in a proportion of patients; the impact of immunosuppressants on generating durable and high-quality memory T cells have not been fully elucidated.
Method: To assess the relevance of immunosuppression profile on vaccine response, we retrospectively analysed the humoral, cellular CD4 and CD8 responses in KTR patients who receiving calcineurin (CNI; tacrolimus, mycophenolate, prednisolone, n=42) compared to mTOR inhibitor-based regimens (mTORi; rapamycin/everolimus, mycophenolate, prednisolone, n=18). In-depth phenotypical and functional of memory T cell were characterised post SARS-CoV-2 vaccination. An additional animal study was also conducted to investigate the effects of rapamycin on T stem cell memory (Tscm) generation.
Result: Compared with patients on CNI, the median of anti-spike IgG titre was 24-fold higher in mTORi groups (AUC 0.2848 vs 6.766; p < 0.05). No significant difference was observed in anti-RBD-IgG titre (33% vs 33%) and neutralisation capacity between CNI and mTORi groups (11.9% vs 20%). Likewise, the spike-specific T cell response was predominantly induced in mTORi groups, 12-fold greater than that of patients with CNI (SFU 520 vs 43/10⁶ cells). Moreover, mTORi groups exhibited overall increase in spike specific T cell population with polyfunctional across naïve-like, central, and effector memory subsets. In animal study, peri-vaccination of rapamycin significantly enhanced the frequency of spike-specific memory T cell pool and associated with increased Tscm (AIM⁺CD44^-CD62L⁺SCA-1⁺).
Conclusion: We suggest that rapamycin selectively boosts T cell immunity by facilitating the generation of full spectrum of memory subsets, including Tscm. Rapamycin could be a potential adjuvant to induce long-lasting immune protection against COVID-19 in transplant recipients.