Immune Responses 6 Months After mRNA-1273 COVID-19 Vaccination and the Effect of a Third Vaccination in Patients with Inborn Errors of Immunity

Abstract

Purpose: Patients with inborn errors of immunity (IEI) are at increased risk of severe coronavirus disease-2019 (COVID-19). Effective long-term protection against COVID-19 is therefore of great importance in these patients, but little is known about the decay of the immune response after primary vaccination. We studied the immune responses 6 months after two mRNA-1273 COVID-19 vaccines in 473 IEI patients and subsequently the response to a third mRNA COVID-19 vaccine in 50 patients with common variable immunodeficiency (CVID).

Methods: In a prospective multicenter study, 473 IEI patients (including X-linked agammaglobulinemia (XLA) (N = 18), combined immunodeficiency (CID) (N = 22), CVID (N = 203), isolated or undefined antibody deficiencies (N = 204), and phagocyte defects (N = 16)), and 179 controls were included and followed up to 6 months after two doses of the mRNA-1273 COVID-19 vaccine. Additionally, samples were collected from 50 CVID patients who received a third vaccine 6 months after primary vaccination through the national vaccination program. SARS-CoV-2-specific IgG titers, neutralizing antibodies, and T cell responses were assessed.

Results: At 6 months after vaccination, the geometric mean antibody titers (GMT) declined in both IEI patients and healthy controls, when compared to GMT 28 days after vaccination. The trajectory of this decline did not differ between controls and most IEI cohorts; however, antibody titers in CID, CVID, and isolated antibody deficiency patients more often dropped to below the responder cut-off compared to controls. Specific T cell responses were still detectable in 77% of controls and 68% of IEI patients at 6 months post vaccination. A third mRNA vaccine resulted in an antibody response in only two out of 30 CVID patients that did not seroconvert after two mRNA vaccines.

Conclusion: A similar decline in IgG titers and T cell responses was observed in patients with IEI when compared to healthy controls 6 months after mRNA-1273 COVID-19 vaccination. The limited beneficial benefit of a third mRNA COVID-19 vaccine in previous non-responder CVID patients implicates that other protective strategies are needed for these vulnerable patients.

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

Fig. 1

Subject enrollment and outcome after four visits. In total, 697 participants signed informed consent (505 IEI patients, 192 controls). Forty-five participants did not complete the four visits (32 IEI patients, 13 controls). The 652 remaining participants (473 IEI patients, 179 controls) were included and described in detail in Table 1. Sixty-four participants (48 IEI patients, 16 controls) were considered as COVID-19 recovered patients. Fifty CVID patients received a third vaccination and donated a blood sample afterwards

Fig. 2

SARS-CoV-2-specific IgG and decay between 28 days and 6 months after second vaccination. (a) S-specific IgG measured by Luminex for controls and different cohorts of IEI patients 28 days and 6 months after the second vaccination. Results at 28 days after the second vaccination were published previously. Results are expressed in binding antibody units per milliliter (BAU/mL). The dotted line is the pre-defined responder cut-off (resp). The percentage of responders is indicated above the graph. Line indicates the geometric mean, error bars indicate the 95% confidence interval. IgG titers at 28 days and 6 months were compared per cohort using the Wilcoxon paired signed rank test. (b) Decay of S-specific IgG expressed as the slope between the two time points determined by an exponential decay model. Only participants with a response 28 days after the second vaccination were included for this analysis. A slope of 1.00 represents no decay in S-specific IgG between the two time points. Slopes between controls and IEI patients were compared using a Wilcoxon rank-sum test with correction for multiple comparisons. In both graphs, the SPAD cohort is indicated with white symbols while the IgG cohort is indicated with orange symbols. S = Spike, XLA = X-linked agammaglobulinemia, CID = Combined Immunodeficiency, CVID = Common Variable Immunodeficiency, IgG = Isolated IgG subclass deficiency ± IgA deficiency, SPAD = Specific polysaccharide antibody deficiency, Undefined = Undefined antibody deficiency, * = P < .05, **** = P < .0001

Fig. 3

SARS-CoV-2 neutralizing antibodies 28 days and 6 months after the second COVID-19 vaccination. Neutralizing antibody titers as 50% inhibitory dilution (ID₅₀) determined by SARS-CoV-2 pseudovirus neutralization assay 28 days and 6 months after the second COVID-19 vaccination expressed as international units/milliliter (IU/mL). Line indicates the geometric mean, error bars indicate the 95% confidence interval. The lower limit of detection (llod) of the pseudovirus neutralization assay is 10 IU/ml. The percentage of participants with detectable neutralizing antibodies is indicated above the graph. Neutralizing antibodies were compared between the two time points using the Wilcoxon paired signed rank test. CID = Combined Immunodeficiency, CVID = Common Variable Immunodeficiency, IgG = Isolated IgG subclass deficiency ± IgA deficiency, SPAD = Specific polysaccharide antibody deficiency, * = P < .05, **** = P < .0001

Fig. 4

SARS-CoV-2-specific T cell responses 28 days and 6 months after the second COVID-19 vaccination. (a) SARS-CoV-2-specific T cell responses measured by an IFN-γ release assay (QIAGEN) after stimulation of whole blood 28 days and 6 months after the second vaccination. Lower limit of detection (llod) is .01 IU/ml and responder cut off (resp) was .15 IU/ml. The percentage of responders is indicated above the graph. Results are expressed as international units/milliliter (IU/mL). Line indicates the geometric mean, error bars indicate the 95% confidence interval. Within each cohort, IFN-γ levels at 28 days and 6 months were compared using Wilcoxon paired signed rank test. (b) Fold change IFN-γ levels between the two timepoints. A fold-change larger than 1 indicates that SARS-CoV-2-specific T-cells responses were lower at 6 months compared to 28 days. Fold changes were compared between the controls and IEI patients using a Wilcoxon rank-sum test with correction for multiple comparisons. In both graphs, the SPAD cohort is indicated with white symbols while the IgG cohort is indicated with orange symbols. XLA = X-linked agammaglobulinemia, CID = Combined Immunodeficiency, CVID = Common Variable Immunodeficiency, IgG = Isolated IgG subclass deficiency ± IgA deficiency, SPAD = Specific polysaccharide antibody deficiency, Undefined = Undefined antibody deficiency, * = P < .05, **** = P < .0001

Fig. 5

SARS-CoV-2 -specific IgG titers and T cell responses 28 days and 6 months after the second COVID-19 vaccination, and 5 weeks after the third vaccination. (a) S-specific IgG titers measured by Luminex is for CVID patients classified as responder (left) or non-responders (right) based on antibody titers 28 days after second vaccination. Displayed timepoints are 28 days after second vaccination (dots), 6 months after the second vaccination (squares) and 5 weeks after third vaccination (triangles). Results are expressed in binding antibody units per milliliter (BAU/mL). The diamond symbols indicate the geometric mean titers, which are also specified above the data points. The dotted line is the responder cut-off (44.8 BAU/ml). (b) SARS-CoV-2-specific T cell responses measured by the QIAGEN interferon-gamma release assay. Lower limit of detection is .01 IU/ml. The dotted line is the pre-defined responder cut-off (.15 IU/ml). Results are expressed as international units/milliliter (IU/mL). The diamond symbols indicate the geometric mean titer. S = spike, CVID = Common Variable Immunodeficiency, ** = P < .01