Specific Cellular and Humoral Immune Responses to the Neoantigen RBD of SARS-CoV-2 in Patients with Primary and Secondary Immunodeficiency and Healthy Donors

Abstract

Patients with antibody deficiency disorders, such as primary immunodeficiency (PID) or secondary immunodeficiency (SID) to B-cell lymphoproliferative disorder (B-CLPD), are two groups vulnerable to developing the severe or chronic form of coronavirus disease caused by SARS-CoV-2 (COVID-19). The data on adaptive immune responses against SARS-CoV-2 are well described in healthy donors, but still limited in patients with antibody deficiency of a different cause. Herein, we analyzed spike-specific IFN-γ and anti-spike IgG antibody responses at 3 to 6 months after exposure to SARS-CoV-2 derived from vaccination and/or infection in two cohorts of immunodeficient patients (PID vs. SID) compared to healthy controls (HCs). Pre-vaccine anti-SARS-CoV-2 cellular responses before vaccine administration were measured in 10 PID patients. Baseline cellular responses were detectable in 4 out of 10 PID patients who had COVID-19 prior to vaccination, perceiving an increase in cellular responses after two-dose vaccination (p < 0.001). Adequate specific cellular responses were observed in 18 out of 20 (90%) PID patients, in 14 out of 20 (70%) SID patients and in 74 out of 81 (96%) HCs after vaccination (and natural infection in some cases). Specific IFN-γ response was significantly higher in HC with respect to PID (1908.5 mUI/mL vs. 1694.1 mUI/mL; p = 0.005). Whereas all SID and HC patients mounted a specific humoral immune response, only 80% of PID patients showed positive anti-SARS-CoV-2 IgG. The titer of anti-SARS-CoV-2 IgG was significantly lower in SID compared with HC patients (p = 0.040), without significant differences between PID and HC patients (p = 0.123) and between PID and SID patients (p =0.683). High proportions of PID and SID patients showed adequate specific cellular responses to receptor binding domain (RBD) neoantigen, with a divergence between the two arms of the adaptive immune response in PID and SID patients. We also focused on the correlation of protection of positive SARS-CoV-2 cellular response to omicron exposure: 27 out of 81 (33.3%) HCs referred COVID-19 detected by PCR or antigen test, 24 with a mild course, 1 with moderate symptoms and the remaining 2 with bilateral pneumonia that were treated in an outpatient basis. Our results might support the relevance of these immunological studies to determine the correlation of protection with severe disease and for deciding the need for additional boosters on a personalized basis. Follow-up studies are required to evaluate the duration and variability in the immune response to COVID-19 vaccination or infection.

Keywords: COVID-19; CVID; SARS-CoV-2 cellular response; SARS-CoV-2 humoral response; antibody deficiency disorders; primary immunodeficiencies; secondary immunodeficiencies.

Figure 1

Schedule of vaccination and SARS-CoV-2 infection of our study population. (A) CVID patients. (B) SID patients. (C) HC patients.

Figure 2

Specific SARS-CoV-2 cellular responses measured by IGRA. (A) Pre-vaccine and post-vaccine anti-SARS-CoV-2 IFN-γ levels in PID patients, with titers significantly lower before the vaccine administration with respect to SARS-CoV-2 post-vaccination levels (p < 0.001). (B) Patients with PID are shown in blue and SID in red compared to immunocompetent controls in green. PID patients exhibited significantly lower IFN-γ anti-SARS-CoV-2 titers than HC (p = 0.005). ** p < 0.01, *** p < 0.001.

Figure 3

Specific anti-SARS-CoV-2 IFN-γ levels in healthy control (HC) subgroups (vaccine showed in blue, natural immune response in yellow and hybrid in green) assessed by IGRA. There was great variability in the HC-vaccine subgroup in comparison with the other subgroups, and the highest titers were observed in the HC-hybrid subgroup.

Figure 4

Antibody anti-SARS-CoV-2 responses measured by chemiluminescent microparticle immunoassay in the three study groups, PID represented with blue triangles, SID with red circles and HC with green squares. SID to B-CLPD mounted significantly lower IgG titers than HC. * Significant differences (p < 0.05).