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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.

SUBMITTER: Netti GS

PROVIDER: S-EPMC9303518 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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

Netti Giuseppe S GS Infante Barbara B Troise Dario D Mercuri Silvia S Panico Maddalena M Spadaccino Federica F Catalano Valeria V Gigante Margherita M Simone Simona S Pontrelli Paola P Gesualdo Loreto L Ranieri Elena E Castellano Giuseppe G Stallone Giovanni G

American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 20220128 5

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 thi ...[more]

PMID: 35038362

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Project description:BackgroundImmunocompromised patients have an increased risk of developing severe COVID disease, as well as a tendency to suboptimal responses to vaccines. The objective of this study was to evaluate the specific cellular and humoral adaptive immune responses of a cohort of kidney transplant recipients (KTR) after 3 doses of mRNA-1273 vaccine and to determinate the main factors involved.MethodsProspective observational study in 221 KTR (149 non infected), 55 healthy volunteers (HV) and 23 dialysis patients (DP). We evaluated anti-spike (by quantitative chemiluminescence immunoassay) and anti-nucleocapsid IgG (ELISA), percentage of TCD4+ and TCD8+ lymphocytes producing IFNγ against S-protein by intracellular flow cytometry after Spike-specific 15-mer peptide stimulation and serum neutralizing activity (competitive ELISA) at baseline and after vaccination.ResultsAmong COVID-19 naïve KTR, 54.2% developed cellular and humoral response after the third dose (vs 100% in DP and 91.7% in HV), 18% only showed cell-mediated response, 22.2% exclusively antibody response and 5.6% none. A correlation of neutralizing activity with both the IgG titer (r=0.485, p<0.001) and the percentage of S-protein-specific IFNγ-producing CD8-T cells (r=0.198, p=0.049) was observed. Factors related to the humoral response in naïve KTR were: lymphocytes count pre-vaccination >1000/mm3 [4.68 (1.72-12.73, p=0.003], eGFR>30 mL/min [7.34(2.72-19.84), p<0.001], mTOR inhibitors [6.40 (1.37-29.86), p=0.018]. Infected KTR developed a stronger serologic response than naïve patients (96.8 vs 75.2%, p<0.001).ConclusionsKTR presented poor cellular and humoral immune responses following vaccination with mRNA-1273. The immunosuppression degree and kidney function of these patients play an important role, but the only modifiable factor with a high impact on humoral immunogenicity after a booster dose was an immunosuppressive therapy including a mTOR inhibitor. Clinical trials are required to confirm these results.

Project description:Abstract BACKGROUND AND AIMS Mortality due to SARS-COV-2 infection in hemodialysis (HD) patients and kidney transplant recipients(KTRs) is high. Despite increased rates of administration of two doses of mRNA vaccines among these vulnerable populations, the adequacy of the respective generated immune responses is reported lower than general population, especially in KTRs. A third booster dose has been officially recommended in these immunocompromised patients while the humoral and cellular immune responses to SARS-COV-2 vaccination remains to be elucidated in HD patients and KTRs. The aim of our study was to investigate the antibody (Ab) response status together with vaccine-induced alterations in circulating lymphocytes subsets, following the administration of three doses of the BNT162b2 vaccine in a cohort of maintenance HD patients and KTRs. METHOD The initial cohort of this prospective study (ClinicalTrials.gov, NCT04932876) included 34 HD patients and 54 KTRs who received two doses of the BNT162b2 (Pfizer–BioNTech). Of this cohort, 24 HD patients and 30 KTRs, who remained free of SARS-CoV2 infection and receive a third dose 6 months after the second dose, were finally analyzed. Lymphocyte subpopulations, including B cells, CD4+and CD8+T cells as well as naïve and memory T lymphocytes subpopulations among others, were analyzed by flow cytometry at four time points, before vaccination (T0), before the second dose (T1), 2 weeks after the second dose (T2) and 2–3 weeks after the third dose (T3). The anti-SARS-CoV2 antibody (Ab) response was assessed by using the ARCHITECT IgG II Quant test (Abbott). Titers >50 arbitrary units (AU)/mL were considered positive for seroconversion at T1 and at T2 and T3. RESULTS Of the initial cohort 31 HD patients (91.8%) and 16 KTRs (29.6%) became seropositive at T2. Of the final cohort (24 HD and 30 KTRs), almost all HD patients (23, 96%) became seropositive since T2 and this finding remained at T3 (Figure 1). In KTRs the percentage of responders was doubled between T2 and T3, T2 9 KTRs (30%) versus T3 18 KTRs (60%) (Figure 1). KTRs who developed Ab at T1 ``respond'' better to the third dose, maximizing the levels of Ab. HD patients who became seropositive at T1 displayed higher CD19+B lymphocytes compared with their seronegative HD counterparts. In HD patients, a positive correlation was established between CD19+B cells counts and Ab titers at all time-points (P < 0.001). In KTRs, Ab at T1 showed an inverse correlation with T+B+NK at T1 (P = 0.006). T2-Ab showed inverse correlation with CD45RA+CD45RO at T0 (P = 0.01) and with CD3+at T3 (P = 0.02). T3-Ab showed positive correlation with CD3+CD16+56+at T2 (P = 0.003) and with CD3-CD16+56+at T3 (P = 0.01). CD19+at T3 correlated positively with Ab at T1 and T3 (P = 0.003 and P = 0.03, respectively). CONCLUSION Our study confirms the improved immunogenicity after the third dose of BNT162b2 vaccine in KTRs. The positive correlation between CD19+B cells and Ab in both groups of patients, more stable and constant in HD patients in comparison with KTR, possibly reflects successful humoral immunity. However, a big proportion of kidney patients remain at high risk for COVID-19 infection considering the new more transmissible variants such as the Omicron variant.

Dataset Information

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

Publications

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

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