Efficacy of COVID-19 mRNA vaccination in patients with autoimmune disorders: humoral and cellular immune response

Abstract

Background: The impact of immunosuppressive therapies on the efficacy of vaccines to SARS-CoV-2 is not completely clarified. We analyzed humoral and T cell-mediated response after COVID-19 mRNA vaccine in immunosuppressed patients and patients with common variable immunodeficiency disease (CVID).

Patients: We enrolled 38 patients and 11 healthy sex- and age-matched controls (HC). Four patients were affected by CVID and 34 by chronic rheumatic diseases (RDs). All patients with RDs were treated by corticosteroid therapy and/or immunosuppressive treatment and/or biological drugs: 14 patients were treated with abatacept, 10 with rituximab, and 10 with tocilizumab.

Methods: Total antibody titer to SARS-CoV-2 spike protein was assessed by electrochemiluminescence immunoassay, CD4 and CD4-CD8 T cell-mediated immune response was analyzed by interferon-γ (IFN-γ) release assay, the production of IFN-γ-inducible (CXCL9 and CXCL10) and innate-immunity chemokines (MCP-1, CXCL8, and CCL5) by cytometric bead array after stimulation with different spike peptides. The expression of CD40L, CD137, IL-2, IFN-γ, and IL-17 on CD4 and CD8 T cells, evaluating their activation status, after SARS-CoV-2 spike peptides stimulation, was analyzed by intracellular flow cytometry staining. Cluster analysis identified cluster 1, namely the "high immunosuppression" cluster, and cluster 2, namely the "low immunosuppression" cluster.

Results: After the second dose of vaccine, only abatacept-treated patients, compared to HC, showed a reduced anti-spike antibody response (mean: 432 IU/ml ± 562 vs mean: 1479 IU/ml ± 1051: p = 0.0034), and an impaired T cell response, compared with HC. In particular, we found a significantly reduced release of IFN-γ from CD4 and CD4-CD8 stimulated T cells, compared with HC (p = 0.0016 and p = 0.0078, respectively), reduced production of CXCL10 and CXCL9 from stimulated CD4 (p = 0.0048 and p = 0.001) and CD4-CD8 T cells (p = 0.0079 and p = 0.0006). Multivariable General Linear Model analysis confirmed a relationship between abatacept exposure and impaired production of CXCL9, CXCL10, and IFN-γ from stimulated T cells. Cluster analysis confirms that cluster 1 (including abatacept and half of rituximab treated cases) showed a reduced IFN-γ response, as well as reduced monocyte-derived chemokines All groups of patients demonstrated the ability to generate specific CD4 T activated cells after spike proteins stimulation. After the third dose of vaccine, abatacept-treated patients acquired the ability to produce a strong antibody response, showing an anti-S titer significantly higher compared to that obtained after the second dose (p = 0.0047), and comparable with the anti-S titer of the other groups.

Conclusions: Patients treated with abatacept showed an impaired humoral immune response to two doses of COVID-19 vaccine. The third vaccine dose has been demonstrated to be useful to induce a more robust antibody response to balance an impaired T cell-mediated one. All patients, exposed to different immunosuppressive drugs, were able to produce specific CD4-activated T cells, after spike proteins stimulation.

Trial registration: Local Ethical Committee NP4187.

Keywords: Abatacept; Autoimmune diseases; COVID-19 vaccination; Interferon-γ; Rituximab; T cell.

Fig. 1

Comparison of plasma levels of antibodies anti-spike protein (A), IFN-γ release by T cells induced by two spike-derived peptides Ag1 (B) and Ag2 (C), effector memory CD8 T cells (D) among the different groups of patients, as indicated, after the second dose of COVID-19 vaccine. The data are shown as box plots (extremes of the box are at the bottom the first and at the top the third quartile, the inner row is the median, and the upper line and lower line are the highest and lowest values). HC, healthy controls; ABA, abatacept; TCZ, tocilizumab; RTX, rituximab; IVIG, intravenous immunoglobulin

Fig. 2

Levels of CXCL10 (A) and CXCL9 (B) released by unstimulated cells (on the left), CD4 T cells stimulated with spike-derived peptide QFN Ag1 (in the middle), and CD4/CD8 T cells stimulated with spike-derived peptide QFN Ag2 (on the right), among the different groups of patients, as indicated, after the second dose of COVID-19 vaccine. The data are shown as box plots (extremes of the box are at the bottom the first and at the top the third quartile, the inner row is the median, and the upper line and lower line are the highest and lowest values). HC, healthy controls; ABA, abatacept; TCZ, tocilizumab; RTX, rituximab; IVIG, intravenous immunoglobulin

Fig. 3

Fold increase levels of CXCL10 (A) and CXCL9 (B) between unstimulated (NS) and CD4 T cells stimulated with spike-derived peptide QFN Ag1, fold increase levels between unstimulated (NS) and CD4/CD8 T cells stimulated with spike-derived peptide QFN Ag2 for each group of patients, as indicated, after the second dose of COVID-19 vaccine. The data are shown as box plots (extremes of the box are at the bottom the first and at the top the third quartile, the inner row is the median, and the upper line and lower line are the highest and lowest values). HC, healthy controls; ABA, abatacept; TCZ, tocilizumab; RTX, rituximab; IVIG, intravenous immunoglobulin

Fig. 4

Comparison of CD4 CD40L/CD137 (A), CD40L/IFN-γ (C), CD40L/IL-2 (E), and CD40L/IL-17 (G) cell percentages between the different treatment groups of patients, after the second dose of COVID-19 vaccine. Percentage of CD40L/CD137 (B), CD40L/IFN-γ (D), CD40L/IL-2 (F), and CD40L/IL-17 (H) in CD4 and CD8 subset for each group of patients. The percentages of CD40L/CD137, CD40L/IL-2, CD40L/IFN-γ, and CD40L/IL-17 cells are calculated respect to CD4 and CD8 total lymphocytes. CD4 and CD8 double positive of unstimulated cells were subtracted from the stimulated ones. The data are shown as box plots (extremes of the box are at the bottom the first and at the top the fourth quartile, the inner row is the median, and the upper line and lower line are the highest and lowest values). HC, healthy controls; ABA, abatacept; TCZ, tocilizumab; RTX, rituximab; IVIG, intravenous immunoglobulin

Fig. 5

Comparison of plasma levels of antibodies anti-spike protein (A), IFN-γ release by T cells induced by two spike-derived peptides Ag1 (B) and Ag2 (C), effector memory CD8 (D) for each group of patients, as indicated, between the second and the third dose of COVID-19 vaccine. The data are shown as box plots (extremes of the box are at the bottom the first and at the top the third quartile, the inner row is the median, and the upper line and lower line are the highest and lowest value). HC, healthy controls; ABA, abatacept; TCZ, tocilizumab; RTX, rituximab; IVIG, intravenous immunoglobulin