Inferior cellular and humoral immunity against Omicron and Delta variants of concern compared with SARS-CoV-2 wild type in hemodialysis patients immunized with 4 SARS-CoV-2 vaccine doses

To the editor:

With the dominance of the most recent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant of concern Omicron (B.1.1.529), the question arises, what is the reason for its high contagiousness in coronavirus disease 2019 (COVID-19)–vaccinated dialysis patients compared with the previous SARS-CoV-2 variants Delta and wild type?

The objective of this study was, therefore, to analyze humoral and cellular immunity directed against the Omicron variant of concern compared with the wild-type or Delta variant of concern in hemodialysis patients (n = 42; Supplementary Table S1) immunized with 4 doses of mRNA COVID-19 vaccine. Titers of neutralizing antibodies (NAbs) against wild type, Delta, and Omicron were estimated by SARS-CoV-2 spike-protein (S-protein) pseudovirus assays. T-cell immunity reactive against wild-type, Delta-derived, and Omicron-derived S-protein was analyzed by multiparameter flow cytometry (Supplementary Figure S1). The analyses were performed 8 to 9 weeks following the fourth doses.

The hemodialysis patients had a clear seroconversion after 4 doses of SARS-CoV-2 vaccination, with a significantly higher titer of NAb against wild type compared with Delta or Omicron S-protein (median [interquartile range]-50% Neutralizing Dose [ND50] = 2117 [663–2560], 759 [276–2560], and 439 [160–1180], respectively). Interestingly, the NAb titer against Delta was significantly higher compared with Omicron-specific NAb (Figure 1 a). Although the number of patients with a detectable S-protein–reactive CD4 T-cell response was nearly identical (40–41 of 42 patients; Supplementary Table S2), the magnitude of response was significantly lower against Omicron- and Delta-derived S-protein compared with wild type (Figure 1b). In contrast, significantly fewer patients showed a detectable S-protein–reactive CD8 T-cell response against Omicron but not Delta compared with wild type (P = 0.0304, Fisher exact test; Supplementary Table S2), although the magnitude of response was not different between all 3 SARS-CoV-2 variants (Figure 1c).

Figure 1.

Comparison of humoral and cellular immunity directed against spike protein (S-protein) derived from Omicron, Delta, and wild-type (WT) variants of concern in hemodialysis patients vaccinated with 4 mRNA coronavirus disease 2019 (COVID-19) vaccine doses. (a) Isolated serum from hemodialysis patients was analyzed for Omicron-, Delta-, and WT-specific neutralizing antibodies (50% Neutralizing Dose [ND50]). (b–f) Isolated peripheral blood mononuclear cells from hemodialysis patients were stimulated for 16 hours with 1 μg/ml severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) S-protein overlapping peptide pools from WT (dark red box plots), Delta (light red box plots), or Omicron (blue box plots). S-protein–reactive T helper cells were identified as life/dead-marker^–CD3⁺CD4⁺CD137⁺CD154⁺ (b), and S-protein–reactive cytotoxic T cells were identified as life/dead-marker^–CD3⁺CD8⁺CD137⁺ (c). Within the S-protein–reactive CD4 T-cell population, antibodies against interferon-γ (IFN-γ) (d), interleukin-2 (IL-2) (e), and tumor necrosis factor (TNF) (f) were used to detect T helper cell 1 cytokine-producing T helper cells. Groups were compared using 2-sided, unpaired Mann-Whitney U test; P ≤ 0.050 was defined as significant.

With regard to the functionality, the frequency of Omicron and Delta S-protein–reactive CD4⁺ T cells producing T helper cell 1 cytokines interferon-γ and tumor necrosis factor was significantly lower compared with wild-type S-protein–reactive CD4+ T cells (Figure 1d and f).

In line with the results from the general populations,^{1 , 2} hemodialysis patients show a clearly decreased humoral and cellular immune response against Omicron compared with SARS-CoV-2 wild type after 4 doses of vaccination. Of interest, Omicron-specific NAb titer was significantly lower compared with Delta-specific NAb, explaining the more efficient evasion of Omicron from neutralizing antibodies³ and its efficient spread in vaccinated individuals.⁴ Because the humoral immune response of dialysis patients strongly benefits from a fourth compared with a third vaccination,⁵ an adjustment of the vaccination procedure should be recommended.

Data Statement

The data will be available on request.