The ROMANOV study found impaired humoral and cellular immune responses to SARS-CoV-2 mRNA vaccine in virus-unexposed patients receiving maintenance hemodialysis

Abstract

Patients on maintenance hemodialysis (MHD), which are at high risk of infection by SARS-CoV-2 virus and death due to COVID-19, have been prioritized for vaccination. However, because they were excluded from pivotal studies and have weakened immune responses, it is not known whether these patients are protected after the "standard" two doses of mRNA vaccines. To answer this, anti-spike receptor binding domain (RBD) IgG and interferon gamma-producing CD4⁺ and CD8⁺ specific-T cells were measured in the circulation 10-14 days after the second injection of BNT162b2 vaccine in 106 patients receiving MHD (14 with history of COVID-19) and compared to 30 healthy volunteers (four with history of COVID-19). After vaccination, most (72/80, 90%) patients receiving MHD naïve for the virus generated at least one type of immune effector, but their response was weaker and less complete than that of healthy volunteers. In multivariate analysis, hemodialysis and immunosuppressive therapy were significantly associated with absence of both anti-RBD IgGs and anti-spike CD8⁺ T cells. In contrast, previous history of COVID-19 in patients receiving MHD correlated with the generation of both types of immune effectors anti-RBD IgG and anti-spike CD8⁺ T cells at levels similar to healthy volunteers. Patients receiving MHD naïve for SARS-Cov-2 generate mitigated immune responses after two doses of mRNA vaccine. Thus, the good response to vaccine of patients receiving MHD with a history of COVID-19 suggest that these patients may benefit from a third vaccine injection.

Keywords: BNT162b2; COVID-19; SARS-CoV-2; hemodialysis; mRNA vaccine.

Graphical abstract

Figure 1

Flowchart of the study. COVID-19, coronavirus disease 2019.

Figure 2

Humoral response of maintenance hemodialysis (MHD) patients totheBNT162b2 vaccine. (a) The titer of IgG anti–receptor-binding domain of the severe acute respiratory syndrome coronavirus 2 spike protein (RBD) was determined by a chemoluminescence assay in 30 healthy volunteers (HVs; triangles) and 106 hemodialyzed patients (HDs; circles) before vaccination (day [D] 0) and 10 to 14 days after the second injection of vaccine. The dashed line represents the limit of detection of the test. Black symbols represent patients with a history of coronavirus disease 2019 (COVID-19) (HVs, n = 4; HDs, n = 14). Crossed circles represent patients on immunosuppressive (IS) drugs. Mann-Whitney test; ∗∗∗∗P < 0.0001. (b) A multivariate analysis was conducted to identify the variables independently associated with seroconversion in the whole cohort (gray square vs. white square). For each variable with a P < 0.10 in multivariate analysis, a forest plot shows the odds ratio and the 95% confidence interval (CI). (c) Comparison of anti-RBD IgG titers in HVs (n = 30), MHD patients with COVID-19 history (n = 14; black circles), MHD patients with IS drugs (n = 12; crossed circles), and naïve MHD patients (n = 80; white circles). The upper dotted line represents the median IgG titer of responder naïve MHD patients. Donuts represent proportions of nonresponders (white), low responders (light gray), and high responders (dark gray). (d) A multivariate analysis was conducted to identify the variables independently associated with a high IgG response to vaccine in naïve MHD patients without IS drugs (gray square vs. white square). For each variable with a P < 0.10 in multivariate analysis, a forest plot shows the odds ratio and the 95% CI. AU, arbitrary unit; Kt/V, dialysis clearance of urea (K) multiplied by dialysis time (t), divided by the volume of distribution of urea (V); NS, not significant.

Figure 3

Cluster of differentiation (CD) 4⁺T-cell response of maintenance hemodialysis (MHD) patients totheBNT162b2 vaccine correlates with humoral response. (a) The secretion of interferon-γ by circulating spike protein-specific CD4⁺ T cells was measured in vitro in healthy volunteers (HVs; n = 30; triangles), MHD patients with coronavirus disease 2019 (COVID-19) history (n = 14; black circles), MHD patients with immunosuppressive (IS) drugs (n = 12; crossed circles), and naïve MHD patients (n = 80; white circles) 10 to 14 days after the second injection of vaccine. Naive MHD patients were divided into 2 groups according to the absence (nonresponders [Non-resp]; n = 11) or presence (responders [Resp]; n = 69) of humoral response. The dashed line represents the threshold of positivity of the test. Mann-Whitney test; ∗P < 0.05, ∗∗P < 0.01, ∗∗∗∗P < 0.0001. (b) The correlation between the titer of anti–receptor-binding domain of the severe acute respiratory syndrome coronavirus 2 spike protein (RBD) IgG and the secretion of interferon-γ by spike-specific CD4⁺ T cells is shown for HVs (n = 30), MHD patients with COVID-19 history (n = 14; black circles), MHD patients with IS drugs (n = 12; crossed circles), and naïve MHD patients (n = 80; white circles). The lower dashed line represents the limit of detection for anti-RBD IgG. The upper dotted line represents the median IgG titer of responder naïve MHD patients. Pie charts represent the percentage of patients with a positive (black) and negative (white) CD4⁺ T-cell response in each stratum of anti-RBD IgG response. χ² Test; ∗∗∗∗P < 0.0001. AU, arbitrary unit; NS, not significant (P > 0.05).

Figure 4

Cluster of differentiation (CD) 8⁺T-cell response of maintenance hemodialysis (MHD) patients totheBNT162b2 vaccine. (a) The secretion of interferon-γ by circulating spike protein-specific CD8⁺ T cells was measured in vitro in healthy volunteers (HVs; n = 30; triangles) and hemodialyzed patients (n = 106; circles) 10 to 14 days after the second injection of the vaccine. Black symbols represent patients with a history of coronavirus disease 2019 (COVID-19). The dashed line represents the threshold of positivity of the test. Mann-Whitney test; ∗∗P < 0.01. (b) Spike-specific CD8⁺ responses in MHD patients were represented for patients with a COVID-19 history (n = 14; black circles), MHD patients with immunosuppressive (IS) drugs (n = 12; crossed circles), and naïve MHD patients (n = 80; white circles), according to the absence (nonresponders [Non-resp]; n = 11) or presence (responders [Resp]; n = 69) of humoral response. Mann-Whitney test; ∗P < 0.05, ∗∗P < 0.01, ∗∗∗P < 0.001, ∗∗∗∗P < 0.0001. (c) A multivariate analysis was conducted to identify the variables independently associated with a CD8⁺ T-cell response to the vaccine in the whole cohort (30 HVs and 106 MHD patients) (gray square as reference group vs. white square). A forest plot shows the odds ratio and the 95% confidence interval (CI) for a variable with P < 0.10 in the multivariate analysis. NS, not significant (P > 0.05).

Figure 5

Profiling the immune response of maintenance hemodialysis (MHD) patients to the standard BNT162b2 vaccination. Color-coded Venn diagrams were used to analyze the logical relation between the individual components of the immune response (IgG, cluster of differentiation [CD] 4⁺ T cells, and CD8⁺ T cells) induced by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine. (a) Profile of immune response in MHD patients with immunosuppressive drugs. (b) Comparison of the profiles of 3 populations: healthy volunteers (n = 30) and MHD patients with (n = 14) and without (n = 80) a medical history of coronavirus disease 2019 (COVID-19). IFN-γ, interferon-γ; RBD, receptor-binding domain of the SARS-CoV-2 spike protein.