ABSTRACT
BACKGROUND: While previous studies described the production of IgG-antibodies in a subgroup of CVID-patients following mRNA-vaccinations with bnt162b2 SARS-CoV2 (CVID responders), the functionality of these antibodies in terms of avidity as measured by the dissociation rate constant (kdis) and the antibody response to booster immunization has not been studied. OBJECTIVE: In CVID responders and healthy individuals the avidity of anti-SARS-CoV-2 serum-antibodies and their neutralization capacity as measured by surrogate virus neutralizing antibodies were analyzed in addition to IgG-, IgM- and IgA-antibody levels and the response of circulating follicular T-helper cells after a third vaccination with BNT162b2 SARS-CoV2 mRNA-vaccine. METHODS: Binding IgG, IgA and IgM serum levels were analyzed by ELISA in CVID-patients responding to the primary vaccination (CVID responders, n=10) and healthy controls (n=41). The binding-avidity of anti-spike antibodies was investigated using biolayer interferometry in combination with biotin-labelled receptor-binding-domain (RBD) of SARS-CoV2 spike-protein and streptavidin-labelled sensors. Antigen-specific recall T-cell responses were assessed by measuring activation-induced markers by flow cytometry. RESULTS: After the third vaccination with BNT162b2 IgG-, IgM and IgA-antibody levels, sVNT levels and antibody avidity were lower in CVID responders as compared to healthy. In contrast αSpike-avidity was comparable in CVID responders and healthy individuals following primary vaccination. Follicular T-helper cell response to booster vaccination in CVID-responders was significantly reduced when compared to healthy individuals. CONCLUSION: Impaired affinity-maturation during booster-response provides new insight into CVID pathophysiology.
ABSTRACT
Previous studies on immune responses following COVID-19 vaccination in patients with common variable immunodeficiency (CVID) were inconclusive with respect to the ability of the patients to produce vaccine-specific IgG antibodies, while patients with milder forms of primary antibody deficiency such as immunoglobulin isotype deficiency or selective antibody deficiency have not been studied at all. In this study we examined antigen-specific activation of CXCR5-positive and CXCR5-negative CD4+ memory cells and also isotype-specific and functional antibody responses in patients with CVID as compared to other milder forms of primary antibody deficiency and healthy controls six weeks after the second dose of BNT162b2 vaccine against SARS-CoV-2. Expression of the activation markers CD25 and CD134 was examined by multi-color flow cytometry on CD4+ T cell subsets stimulated with SARS-CoV-2 spike peptides, while in parallel IgG and IgA antibodies and surrogate virus neutralization antibodies against SARS-CoV-2 spike protein were measured by ELISA. The results show that in CVID and patients with other milder forms of antibody deficiency normal IgG responses (titers of spike protein-specific IgG three times the detection limit or more) were associated with intact vaccine-specific activation of CXCR5-negative CD4+ memory T cells, despite defective activation of circulating T follicular helper cells. In contrast, CVID IgG nonresponders showed defective vaccine-specific and superantigen-induced activation of both CD4+T cell subsets. In conclusion, impaired TCR-mediated activation of CXCR5-negative CD4+ memory T cells following stimulation with vaccine antigen or superantigen identifies patients with primary antibody deficiency and impaired IgG responses after BNT162b2 vaccination.