Improved cellular and humoral immunity upon a second BNT162b2 and mRNA-1273 boost in prime-boost vaccination no/low responders with end-stage renal disease

To the editor:

Patients with end-stage renal disease (ESRD) develop inefficient immune responses upon vaccination and have a high risk of developing severe coronavirus disease 2019 (COVID-19). The globally expanding severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant of concern (VOC), B.1.6.17.2/Delta, evades immune responses and might constitute a particular threat to these patients.1, 2, 3

Herein, we evaluated the efficacy of a third dose (second boost) by BNT162b2 (Pfizer–BioNTech) or mRNA-1273 (Moderna) mRNA vaccines (Supplementary Table S1 and Supplementary Figure S1) in ESRD patients with no response/low response (NR/LR) after prime-boost BNT162b2 vaccination and compared with ESRD with high response (HR) following the regular prime-boost vaccination. Enzyme-linked immunosorbent assay, pseudovirus neutralization assay, and flow cytometry were applied to assess humoral and cellular immunity against the spike (S) protein of SARS-CoV-2 wild type (WT-S) and the Delta-VOC (Delta-VOC-S) before and 3 to 5 weeks following the last booster vaccination.

In NR/LR, 20 of 23 patients developed high-binding WT-S antibody titers (Figure 1 a and Supplementary Figure S2A), with neutralizing capacity in 19 of 22 patients. The third vaccination led to an increase in WT-S protein-reactive CD4⁺ T cells (Figure 1b) without differences between the applied vaccines (Supplementary Figure S2B and C). The higher frequency of S-reactive T follicular helper (Tfh) cells was the only difference observed in mRNA-1273–boosted patients (Supplementary Figure S2D).

Figure 1.

The effect of a third severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccination boost. Patients with no response/low response (NR/LR) after a regular prime-boost SARS-CoV-2 mRNA vaccination (BNT162b2; Pfizer–BioNTech) scheme were given a second boost (3 doses). Patients with antibody titres >250 IU/ml after the first boost served as control group (high response [HR], 2 doses). (a–h) Comparison within NR/LR. (a) Antibody titers before and 3 to 5 weeks after the second SARS-CoV-2 mRNA vaccine boost. (b–d) Analysis of vaccine-reactive T-cell immunity following stimulation with SARS-CoV-2 Spike (S)-protein overlapping peptide pools. (b) The frequency of antigen-specific CD4⁺ T cells. (c) The frequency of antigen-specific CD8⁺ T cells. (d) The frequency of activated T follicular helper (Tfh) cells, as defined by CXC chemokine receptor 5 (CXCR5) expression. (e,f) Analysis of T-cell immunity following stimulation with (Delta-variant of concern [VOC]–S) peptides (Delta) and corresponding peptides from wild type (WT-S; Wuhan-1 isolate). (e) The frequency of antigen-specific CD4⁺ T cells. (f) The frequency of antigen-specific CD8⁺ T cells. (g) A comparison of neutralizing antibodies against pseudoviruses bearing WT-S or Delta-VOC-S. (h) The correlation between the activation of CD4⁺ T cells and neutralization. White indicates no detection of humoral (antibody) or cellular (T-cell) immunity. (i–o) A comparison between HR (2 doses) and NR/LR (3 doses). (i) Antibody titers 3 to 5 weeks after the second SARS-CoV-2 mRNA vaccine boost. (j,k) Analysis of vaccine-reactive T-cell immunity following stimulation with SARS-CoV-2–S-protein overlapping peptide pools. (j) The frequency of antigen-specific CD4⁺ T cells. (k) The frequency of antigen-specific CD8⁺ T cells. (l) The frequency of activated Tfh cells, as defined by CXCR5 expression. (m–o) The analysis of T-cell immunity following stimulation with Delta-VOC-S peptides (Delta) and the corresponding peptides from WT-S (Wuhan-1 isolate). (m) The frequency of antigen-specific CD4⁺ T cells. (n) The frequency of antigen-specific CD8⁺ T cells. (o) Neutralizing antibodies against pseudoviruses bearing WT-S or Delta-VOC-S. The box plots indicate the 75th, 50th, and 25th quantiles, and the whiskers indicate 1.5× the interquartile range. ∗P ≤ 0.05, ∗∗∗P ≤ 0.001, ∗∗∗∗P ≤ 0.0001. D0, day 0; D14, day 14; ND50, 50% neutralization dose; NS, not significant.

Cellular immunity against WT-S and Delta-VOC-S was comparable irrespectively of helper or cytotoxic T cells or vaccine type (Figure 1e and f and Supplementary Figure S2E and F). In contrast, only 8 had neutralizing antibodies against Delta-VOC-S (Figure 1g). A clear association between cellular and humoral immunity was observed for each patient (Figure 1h). More important, when comparing the data obtained from NR/LR following the third dose with ESRD HR after the second dose, overall, superior results in cellular immunity and WT neutralizing capacity were observed. Although S-binding antibody titers and S-reactive CD4⁺ T cells were comparable between both cohorts (Figure 1i and j), WT neutralizing capacity and S-WT– and Delta-reactive CD8⁺ T cells and S-reactive Tfh cells were significantly higher in NR/LR after the second booster (third dose) compared with HR requiring only 1 booster (2 doses; Figure 1g, h, n, and o).

Our data demonstrate that patients with ESRD can benefit from a second vaccination boost by improving their cellular and humoral immunity not only to the vaccination-specific strain but also against the globally expanding Delta-VOC.