Immunogenicity of the mRNA-1273 COVID-19 vaccine in adult patients with inborn errors of immunity

Abstract

Background: Patients with inborn errors of immunity (IEI) are at increased risk of severe coronavirus disease-2019 (COVID-19). Effective vaccination against COVID-19 is therefore of great importance in this group, but little is known about the immunogenicity of COVID-19 vaccines in these patients.

Objectives: We sought to study humoral and cellular immune responses after mRNA-1273 COVID-19 vaccination in adult patients with IEI.

Methods: In a prospective, controlled, multicenter study, 505 patients with IEI (common variable immunodeficiency [CVID], isolated or undefined antibody deficiencies, X-linked agammaglobulinemia, combined B- and T-cell immunodeficiency, phagocyte defects) and 192 controls were included. All participants received 2 doses of the mRNA-1273 COVID-19 vaccine. Levels of severe acute respiratory syndrome coronavirus-2-specific binding antibodies, neutralizing antibodies, and T-cell responses were assessed at baseline, 28 days after first vaccination, and 28 days after second vaccination.

Results: Seroconversion rates in patients with clinically mild antibody deficiencies and phagocyte defects were similar to those in healthy controls, but seroconversion rates in patients with more severe IEI, such as CVID and combined B- and T-cell immunodeficiency, were lower. Binding antibody titers correlated well to the presence of neutralizing antibodies. T-cell responses were comparable to those in controls in all IEI cohorts, with the exception of patients with CVID. The presence of noninfectious complications and the use of immunosuppressive drugs in patients with CVID were negatively correlated with the antibody response.

Conclusions: COVID-19 vaccination with mRNA-1273 was immunogenic in mild antibody deficiencies and phagocyte defects and in most patients with combined B- and T-cell immunodeficiency and CVID. Lowest response was detected in patients with X-linked agammaglobulinemia and in patients with CVID with noninfectious complications. The assessment of longevity of immune responses in these vulnerable patient groups will guide decision making for additional vaccinations.

Keywords: CID; CVID; Inborn errors of immunity; SARS-CoV-2; T-cell response; XLA; antibody response; immunogenicity; mRNA-1273 COVID-19 vaccine; primary immunodeficiency disorders.

Fig 1

Subject enrollment and outcome after 3 visits. In total, 697 patients signed informed consent (505 patients with IEI, 192 controls). Fifteen participants did not complete the 3 visits (10 patients with IEI, 5 controls). A total of 51 participants (39 patients with IEI, 12 controls) were considered as COVID-19 recovered patients and are discussed separately. The 631 remaining participants (456 patients with IEI, 175 controls) are described in detail in Table I.

Fig 2

SARS-CoV-2–specific binding antibodies. A, Levels (GMT ± 95% CI) of total RBD-specific immunoglobulins at baseline (pre), after vaccination 1 (post 1), and after vaccination 2 (post 2) in all different patients with PID. Symbols show individual data points, violin plots reflect data distribution, and lines connect the GMT. B, Comparison of total RBD-specific immunoglobulins (GMT ± 95% CI) after vaccination 1 (left panel) and after vaccination 2 (right panel) between groups. Lower level of detection is a ratio of 0, and responder (resp) cutoff is a ratio of 1 (black dotted line). A ratio of 18 is the maximum dynamic range of the assay. Number of participants above responder cutoff is indicated beneath the x-axis. C, Comparison of S-specific antibodies (GMT ± 95% CI) after vaccination 2 between groups. LLoD is 1 BAU/mL, and responder (resp) cutoff is set at 22.87 BAU/mL (black dotted line). Number of participants above responder cutoff is indicated beneath the x-axis. Patients with IgG deficiencies and patients with SPAD are combined in panels B and C, but the original color coding (A) is maintained. Color coding is the same in all (Online Repository) figures. def, Deficiency; LLoD, lower level of detection; phag, phagocyte; PID, primary immunodeficiency; undef, undefined.

Fig 3

SARS-CoV-2–specific neutralizing antibodies. A, Comparison of neutralizing antibodies (GMT ± 95% CI) determined by pseudovirus neutralization test after vaccination 2 between groups. LLoD is a 10 IU/mL. B, Comparison of neutralizing antibodies (GMT ± 95% CI) determined by PRNT after vaccination 2 between groups. LLoD is 14.29 IU/mL, and responder (resp) cutoff is 28.57 IU/mL (black dotted line). Number of participants above responder cutoff is indicated beneath the x-axis. Patients with IgG deficiencies and patients with SPAD are combined, but the original color coding (Fig 2, A) is maintained. LLoD, Lower level of detection; PRNT, plaque reduction neutralization test; VNT, virus neutralisation test.

Fig 4

SARS-CoV-2-T-cell responses. A, Levels of S-specific T cells (GMT ± 95% CI) determined by QuantiFERON assay (Ag2) at baseline (pre), after vaccination 1 (post 1), and after vaccination 2 (post 2) in patients with IEI at 2 inclusion sites (Erasmus MC and LUMC). LLoD is 0.01 IU/mL, and responder (resp) cutoff is set at 0.15 IU/mL (black dotted line). Symbols show individual data points, violin plots reflect data distribution, and lines connect the GMT. B, Comparison of S-specific T-cell responses (GMT ± 95% CI) determined by QuantiFERON assay (Ag2) after vaccination 1 (left panel) and after vaccination 2 (right panel) between groups. LLoD is 0.01 IU/mL, and responder (resp) cutoff is 0.15 IU/mL (black dotted line). Number of participants above responder cutoff is indicated beneath the x-axis. def, Deficiency; LLoD, lower level of detection; phag, phagocyte; LLoD, Lower level of detection; undef, undefined.