mTOR inhibitors improve both humoral and cellular response to SARS-CoV-2 messenger RNA BNT16b2 vaccine in kidney transplant recipients

Abstract

Kidney transplant recipients (KTRs) have been considered as patients at higher risk of SARS‐CoV‐2‐related disease severity, thus COVID‐19 vaccination was highly recommended. However, possible interferences of different immunosuppression with development of both humoral and T cell–mediated immune response to COVID‐19 vaccination have not been determined. Here we evaluated the association between mTOR‐inhibitors (mTOR‐I) and immune response to mRNA BNT162b2 (Pfizer‐BioNTech) vaccine in KTR. To this aim 132 consecutive KTR vaccinated against COVID‐19 in the early 2021 were enrolled, and humoral and T cell–mediated immune response were assessed after 4–5 weeks. Patients treated with mTOR‐I showed significantly higher anti‐SARS‐CoV‐2 IgG titer (p = .003) and higher percentages of anti‐SARS‐CoV‐2 S1/RBD Ig (p = .024), than those without. Moreover, SARS‐CoV‐2‐specific T cell–derived IFNγ release was significantly increased in patients treated with mTOR‐I (p < .001), than in those without. Multivariate analysis confirmed that therapy with mTOR‐I gained better humoral (p = .005) and T cell–mediated immune response (p = .005) in KTR. The presence of mTOR‐I is associated with a better immune response to COVID‐19 vaccine in KTR compared to therapy without mTOR‐I, not only by increasing vaccine‐induced antibodies but also by stimulating anti‐SARS‐CoV‐2 T cell response. These finding are consistent with a potential beneficial role of mTOR‐I as modulators of immune response to COVID‐19 vaccine in KTR.

Enhanced Humoral Immune Response After COVID-19 Vaccination in Elderly Kidney Transplant Recipients on Everolimus Versus Mycophenolate Mofetil–containing Immunosuppressive Regimens

“…16 Also, better humoral response rates after 2 COVID-19 vaccinations for KTRs on mTOR inhibitors have been described before. 7,12,17,18 Recently, a third COVID-19 mRNA vaccination has been shown to be effective and safe in several studies in KTRs, 17,19,20 including a randomized, clinical trial, increasing seroresponse by approximately 43% to 55% 20 ; however, also in these studies, a significant percentage of KTRs remained seronegative, and they are in striking contrast with the promising results of our randomized study, showing that all EVR-treated patients were seropositive after 3 COVID-19 vaccinations. These data warrant further research into the effects of an EVR-containing immunosuppressive regimen on the (COVID-19) vaccination response and clinical outcomes of COVID infection in vaccinated organ transplant recipients on EVR.…”

“…Also, methods differed between the studies. Whereas we used a sensitive ELISpot assay, which is not affected by in vitro activity of immunosuppressive drugs, an IFN-ɣ release assay was used in the study described by Netti et al 18 Finally, more in-depth studies into additional functional and phenotypic characteristics of the T cells may reveal differences between regimes we now could not observe.…”

“… 16 Also, better humoral response rates after 2 COVID-19 vaccinations for KTRs on mTOR inhibitors have been described before. 7 , 12 , 17 , 18 …”

Impact of COVID-19 on the liver and on the care of patients with chronic liver disease, hepatobiliary cancer, and liver transplantation: An updated EASL position paper

“…mTor inhibitor use in renal transplant recipients has been shown to be associated with improved humoral and T cell responses after COVID-19 vaccination [ 247 ]. This may be linked to the immunomodulatory effect of mTOR inhibitors on memory CD8+ and CD4+ T cells which in turn promote the enhancement of memory precursor effector cells.…”

How Vaccinations Changed the Outcome of COVID-19 Infections in Kidney Transplant Patients: Single-Center Experience

“…However, only one needed hospitalization during both infections. Finally, a favorable infection outcome was demonstrated in 24 patients at higher risk of complications, treated with monoclonal therapy after immunosuppression reduction, which remains of paramount importance while managing the infection [ 11 , 12 ]. Treatments have been proven to be safe so far.…”