mTOR inhibition improves the formation of functional T cell memory following COVID-19 vaccination of kidney transplant recipients

Abstract

Inadequate immune response to vaccination is a long-standing problem faced by immunosuppressed kidney transplant recipients (KTRs), requiring novel strategies to improve vaccine efficacy. In this study, the potential of mechanistic target of rapamycin inhibitors (mTORi) to improve T cell responses to COVID-19 vaccination was investigated. Following primary vaccination with adenoviral (ChAdOx1) or mRNA (BNT162b2) COVID-19 vaccines, KTRs receiving rapamycin demonstrated T cell responses greater than those of healthy individuals, characterized by increased frequencies of vaccine-specific central memory, effector memory and TEMRA T cells, in both the CD4+ and CD8+ compartments. Relative to standard-of-care triple therapy, mTORi-based therapy was associated with a 12-fold greater functional T cell response to primary vaccination of KTRs. The use of rapamycin to augment T cell responses to COVID-19 booster (third dose) vaccination was next investigated in a randomized, controlled trial. Immunosuppression modification with rapamycin was feasible and well-tolerated, but did not improve vaccine-specific T cell responses in this cohort. To understand the parameters for effective use of rapamycin as a vaccine adjuvant, mice were treated with rapamycin before primary or booster vaccination with ancestral and/or Omicron COVID-19 vaccines. Supporting the findings from KTRs, significant enhancement of functional and stem-like memory T cell responses was observed when rapamycin was administered from the time of primary, rather than booster, vaccination. Collectively, a positive effect of mTOR inhibitors on vaccine-induced T cell immunity against COVID-19 in humans was demonstrated.

Immune profiling of COVID-19 vaccine responses in people with multiple sclerosis on B cell-depleting therapy

“…IFNγ ELISpots were performed in-house and counts are comparable with previous reports from our group. [54][55][56] Briefly, multiscreen-IP HTS plates (Merck Millipore) were coated with antihuman IFN-γ (clone 2G1, Thermo Fisher). PBMCs were thawed by dropwise addition of complete media (20% FCS) with Benzonase® nuclease (Merck Millipore) to prevent aggregation, and stimulated for 18h with 4 pools of overlapping peptides spanning the entire length of the spike glycoprotein of the USA-WA1/2020 strain.…”