Mechanistic Target of Rapamycin Inhibitors and Vaccine Response in Kidney Transplant Recipients

Key Points Mechanistic target of rapamycin (mTOR) inhibitor–based immunosuppression was associated with an improved T-cell response to vaccination in kidney transplant recipients. Mice treated with an mTOR inhibitor exhibited improved T-cell responses to booster vaccination. Switching low and nonresponder kidney transplant recipients to an mTOR inhibitor did not improve T-cell response to a booster vaccination. Background Failure to develop protective immunity in response to vaccination is common among kidney transplant recipients, rendering them susceptible to severe infection. Novel strategies are required. Here, we investigated the potential of mechanistic target of rapamycin (mTOR) inhibitors to improve vaccine responses. Methods Humoral and cellular responses to primary coronavirus disease 2019 (COVID-19) vaccination (ChAdOx1 or BNT162b2) were assessed for kidney transplant recipients receiving mTOR inhibitor–based (mTOR inhibitor, mycophenolate, prednisolone, n =15) and standard-of-care (tacrolimus, mycophenolate, prednisolone, n =40) immunosuppression, and healthy cohabitants ( n =71), in a prospective observational study. Findings were validated and mechanisms explored in mice. Low/nonresponding kidney transplant recipients receiving standard-of-care immunosuppression ( N =54) were then randomized 1:1 to switch from mycophenolate to sirolimus or remain on standard of care for 4 weeks before receiving COVID-19 booster vaccination. Augmentation of immunity to COVID-19 was assessed as the primary outcome measure. Results A 12-fold greater IFN γ T-cell response to primary vaccination was observed in kidney transplant recipients receiving mTOR inhibitor–based versus standard-of-care immunosuppression (520 versus 43 spot-forming units/10 6 cells, P < 0.001). A greater frequency of functional memory T cells in the mTOR inhibitor group was observed for both the CD4 + (0.20% versus 0.05%, P < 0.001) and CD8 + (0.35% versus 0.07%, P = 0.006) compartments by flow cytometry, and kidney transplant recipients receiving mTOR inhibitor–based immunosuppression produced greater frequencies of severe acute respiratory syndrome coronavirus 2–specific CD4 + T cells than healthy cohabitants (1.17% versus 0.48%, P = 0.03). In mice, sirolimus treatment enhanced both recall and de novo T-cell responses to homologous and Omicron-specific booster vaccines. Switch from mycophenolate to sirolimus was well tolerated; however, no significant difference was observed in the proportion of kidney transplant recipients in the intervention and control arms that achieved protective virus neutralization (10/25 [40%] versus 9/21 [43%], respectively, P = 0.85) nor in T-cell response to vaccination ( P = 0.89). Conclusions mTOR inhibition was associated with improved T-cell memory formation in kidney transplant recipients; however, this effect was not reproduced by a short-term mycophenolate to sirolimus switch strategy. Clinical Trial registry name and registration number: Australian New Zealand Clinical Trials Registry, ACTRN12621001412820.