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 TEMRAT 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.One Sentence Summary Rapamycin use at the time of primary COVID-19 vaccination augments the formation of functional, vaccine-specific T cell memory in immunosuppressed kidney transplant recipients..
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Preprint| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
bioRxiv.org - (2023) vom: 09. Dez. Zur Gesamtaufnahme - year:2023 |
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| Sprache: |
Englisch |
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| Links: |
Volltext [kostenfrei] |
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| doi: |
10.1101/2023.03.27.23287773 |
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| PPN (Katalog-ID): |
XBI039109550 |
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| 520 | |a 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 TEMRAT 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.One Sentence Summary Rapamycin use at the time of primary COVID-19 vaccination augments the formation of functional, vaccine-specific T cell memory in immunosuppressed kidney transplant recipients. | ||
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