Humoral and cellular immunity to SARS-CoV-2 vaccination in renal transplant versus dialysis patients: A prospective, multicenter observational study using mRNA-1273 or BNT162b2 mRNA vaccine

Abstract

Background: Dialysis and kidney transplant patients are vulnerable populations for COVID-19 related disease and mortality.

Methods: We conducted a prospective study exploring the eight week time course of specific cellular (interferon-γ release assay and flow cytometry) or/and humoral immune responses (ELISA) to SARS-CoV-2 boost vaccination in more than 3100 participants including medical personnel, dialysis patients and kidney transplant recipients using mRNA vaccines BNT162b2 or mRNA-1273.

Results: SARS-CoV-2-vaccination induced seroconversion efficacy in dialysis patients was similar to medical personnel (> 95%), but markedly impaired in kidney transplant recipients (42%). T-cellular immunity largely mimicked humoral results. Major risk factors of seroconversion failure were immunosuppressive drug number and type (belatacept, MMF-MPA, calcineurin-inhibitors) as well as vaccine type (BNT162b2 mRNA). Seroconversion rates induced by mRNA-1273 compared to BNT162b2 vaccine were 97% to 88% (p < 0.001) in dialysis and 49% to 26% in transplant patients, respectively. Specific IgG directed against the new binding domain of the spike protein (RDB) were significantly higher in dialysis patients vaccinated by mRNA-1273 (95%) compared to BNT162b2 (85%, p < 0.001). Vaccination appeared safe and highly effective demonstrating an almost complete lack of symptomatic COVID-19 disease after boost vaccination as well as ceased disease incidences during third pandemic wave in dialysis patients.

Conclusion: Dialysis patients exhibit a remarkably high seroconversion rate of 95% after boost vaccination, while humoral response is impaired in the majority of transplant recipients. Immunosuppressive drug number and type as well as vaccine type (BNT162b2) are major determinants of seroconversion failure in both dialysis and transplant patients suggesting immune monitoring and adaption of vaccination protocols.

Keywords: BNT162b2; COVID-19; SARS-CoV-2 vaccination; clinical decision-making; dialysis patients; epidemiology; guidelines; humoral and cellular immune response; kidney transplant recipients; mRNA-1273; medical personnel; tozinameran.

Fig. 1

Study cohort * Symptomatic participants = clinical infection, PCR proven ** Asymptomatic participants before 1st vaccination = IgG against Spike S1 ≥ 35•2 BAU/ml or IgG against NCP ≥ 1•1 ratio *** Participants with symptomatic [clinical infection, PCR proven] or asymptomatic [IgG NCP ≥ 1.1 ratio] SARS-CoV-2 infection during or after vaccination period were analyzed separately for the assessment of safety and serological efficacy and are added to the pure vaccination cohort in the corresponding analysis (clinical vaccination cohort). T0 = before first vaccination; T1 = 3–4 weeks after first vaccination; T2 = 4–5 weeks after first vaccination; Analysis of humoral response included measurement of IgA and IgG antibodies against the SARS-CoV-2 S1 protein at time point T0 and additionally IgG antibodies against the novel binding domain S1/RDB of the ACE2 receptor at time point T2. At both time points, additional IgG antibodies against the SARS-CoV-2 nucleocapsid (NCP) were measured. Analysis of the cellular immune response included deep immunophenotyping by FACS analysis and interferon-gamma release assays. Patients in the FACS analysis were all included in the group of IGRA measurements (reciprocal not true). All consented participants from 4 centers adjacent to the study coordination center were selected for IGRA measurement (logistic reasons). The selection took into account the respective number of patients per group (MP/DP/KR) and vaccine type and center. One of the 4 centers with T-cell isolation did not participate in PBMC isolation and thus deep immunophenotyping. For the latter, participants were selected from all 3 groups in which a sufficient number of cells (at least 10⁷/time point and participant) was ensured for the planned analyses at least at the time points T0 and T2 before cryopreservation and after PBMC isolation (technical reasons). BNT162b2 and mRNA-1273 account for the distinct vaccine types. Different indications of numbers stand for the corresponding case numbers in the corresponding subgroups.

Fig. 2

Analysis of SARS-CoV-2-reactive CD4+ T-cell helper response by multi-parameter flow cytometry. a) Incidence of SARS-CoV-2-reactive CD4+ T cell responders. A T-cell response is defined as a twofold increase or more in the frequency of activated T cells between T0 and T1 or T2. b) Kinetics of activated Spike-reactive CD4+ T helper cells at and following vaccination. Shown frequencies are after correction for background activation. c) Magnitude of SARS-CoV-2 Spike-reactive CD4+ T helper cell response in MP, DP, and KTR cohorts at different time points. Shown frequencies are after correction for background activation. d) Spike-reactive cytokine-producing CD4+ T cells detected at T2 in study cohorts. Depicted is the total frequency of cytokine IFNg, TNF, IL2 or Granzyme B producing CD4+ T cells, which produce only one cytokine (1P), or simultaneously produce two (2P), three or four (3P or 4P) cytokines. e) Magnitude of SARS-CoV-2 Spike-reactive CD4+ T helper cell response in humoral responders and non-responders as defined by IgG serology. f) Incidence of SARS-CoV2-reactive CD4+ T helper cell responders in DP and KTR patients vaccinated by BNTb162b or mRNA-1273 vaccine. Depicted are the responses at T2. Asterisks indicate the level of significance for the paired t-test (b) and Mann-Whitney U test (c and e): * p ≤ 0.05, ** p ≤ 0.01, *** p ≤ 0.001.

Fig. 2

Analysis of SARS-CoV-2-reactive CD4+ T-cell helper response by multi-parameter flow cytometry. a) Incidence of SARS-CoV-2-reactive CD4+ T cell responders. A T-cell response is defined as a twofold increase or more in the frequency of activated T cells between T0 and T1 or T2. b) Kinetics of activated Spike-reactive CD4+ T helper cells at and following vaccination. Shown frequencies are after correction for background activation. c) Magnitude of SARS-CoV-2 Spike-reactive CD4+ T helper cell response in MP, DP, and KTR cohorts at different time points. Shown frequencies are after correction for background activation. d) Spike-reactive cytokine-producing CD4+ T cells detected at T2 in study cohorts. Depicted is the total frequency of cytokine IFNg, TNF, IL2 or Granzyme B producing CD4+ T cells, which produce only one cytokine (1P), or simultaneously produce two (2P), three or four (3P or 4P) cytokines. e) Magnitude of SARS-CoV-2 Spike-reactive CD4+ T helper cell response in humoral responders and non-responders as defined by IgG serology. f) Incidence of SARS-CoV2-reactive CD4+ T helper cell responders in DP and KTR patients vaccinated by BNTb162b or mRNA-1273 vaccine. Depicted are the responses at T2. Asterisks indicate the level of significance for the paired t-test (b) and Mann-Whitney U test (c and e): * p ≤ 0.05, ** p ≤ 0.01, *** p ≤ 0.001.

Fig. 2

Analysis of SARS-CoV-2-reactive CD4+ T-cell helper response by multi-parameter flow cytometry. a) Incidence of SARS-CoV-2-reactive CD4+ T cell responders. A T-cell response is defined as a twofold increase or more in the frequency of activated T cells between T0 and T1 or T2. b) Kinetics of activated Spike-reactive CD4+ T helper cells at and following vaccination. Shown frequencies are after correction for background activation. c) Magnitude of SARS-CoV-2 Spike-reactive CD4+ T helper cell response in MP, DP, and KTR cohorts at different time points. Shown frequencies are after correction for background activation. d) Spike-reactive cytokine-producing CD4+ T cells detected at T2 in study cohorts. Depicted is the total frequency of cytokine IFNg, TNF, IL2 or Granzyme B producing CD4+ T cells, which produce only one cytokine (1P), or simultaneously produce two (2P), three or four (3P or 4P) cytokines. e) Magnitude of SARS-CoV-2 Spike-reactive CD4+ T helper cell response in humoral responders and non-responders as defined by IgG serology. f) Incidence of SARS-CoV2-reactive CD4+ T helper cell responders in DP and KTR patients vaccinated by BNTb162b or mRNA-1273 vaccine. Depicted are the responses at T2. Asterisks indicate the level of significance for the paired t-test (b) and Mann-Whitney U test (c and e): * p ≤ 0.05, ** p ≤ 0.01, *** p ≤ 0.001.