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.
Highlights
COVID-19 (Coronavirus Disease-2019) is caused by infection with severe acute respiratory syndrome (SARS)-CoV-2, a novel coronavirus discovered at the end of 2019 [1]
IgG responses in common variable immunodeficiency (CVID) patients as a group were significantly lower as compared to both healthy controls and oPAD patients (Figure 2A); sixteen (51.5%) of 31 CVID patients showed anti-S-IgG antibodies below the detection limit or very low to borderline, while 15 (48.4%) CVID patients produced levels of IgG antibodies comparable to healthy controls (HC) (Figure 2A)
Anti-spike IgA levels were significantly higher in oPAD patients or healthy controls after vaccination as compared to values obtained in unvaccinated individuals, but there was a trend towards lower levels in oPAD patients as compared to healthy controls (IgA anti-spike, median ratio: HC 9.10; oPAD 3.25), and seven oPAD patients failed to produce any IgA antibodies, including two patients with IgA deficiency (Figure 2B)
Summary
COVID-19 (Coronavirus Disease-2019) is caused by infection with SARS-CoV-2, a novel coronavirus discovered at the end of 2019 [1]. Among the PAD group patients with common variable immunodeficiency (CVID) complicated by inflammatory, autoimmune or respiratory comorbidities were most vulnerable to develop severe COVID-19 [6,7,8]. CVID is the most common clinically severe form of primary antibody deficiency, characterized by a severe impairment to produce pathogen-specific IgG antibodies [9]. Other forms of PAD (oPAD) show a persistent and marked decrease of at least one of the serum immunoglobulins and/or IgG-subclasses and/or a specific antibody deficiency to polysaccharide antigens but have an intact ability to produce IgG antibodies after vaccination with T-dependent protein antigens [10]. Clinical presentation of these patients is often mild as compared to CVID, severe disease can still develop [11] and these patients can present with severe COVID-19 [8]
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