Antigen-Specific CD4+ T-Cell Activation in Primary Antibody Deficiency After BNT162b2 mRNA COVID-19 Vaccination

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.

Mortality in Severe Antibody Deficiencies Patients during the First Two Years of the COVID-19 Pandemic: Vaccination and Monoclonal Antibodies Efficacy

“…Differently, additional booster immunizations could lead to enhancement of SARS-CoV-2 circulating T follicular helper cells as in vaccination against influenza [21], and vaccine booster doses might render patients' antigen-specific T cells more responsive to stimulation or increase their numbers. Interestingly, our patients have similar immunological conditions to the low-responder convalescents described in a recent paper [25] who did not report any relevant symptoms during SARS-CoV-2 infection. Apart from T cell contribution, the lack of induction of adaptive B cell immunity might also be compensated by functional innate immunity cells [26,27].…”

Cellular Immune Response to BNT162b2 mRNA COVID-19 Vaccine in a Large Cohort of Healthcare Workers in a Tertiary Care University Hospital

“…Similarly, the self-reported occurrence of autoimmune diseases also tended to be associated to lower levels of cellular immunity, whereas no significant association was found for serology in our previous study [ 15 ]. Although we have to consider the limit of self-reporting, it is likely that impairment in immune responses in immune-mediated diseases, as well as specific therapies, may play a relevant role in vaccine immunogenicity, as already described for example in multiple sclerosis and immune-mediated inflammatory rheumatic diseases [ 49 , 50 , 51 , 52 , 53 ] or immunodeficiency [ 54 , 55 ].…”

COVID-19 and Inborn Errors of Immunity

“…Another important aspect regarding the studies that assessed the antibody responses to the COVID-19 vaccine in patients with CVID is the definition of the clinical and immunological factors associated with increased risk of seroconversion failure after two vaccine doses. These risk factors are specified in Table 1 and included older patients’ age ( 120 ), history of autoimmunity ( 117 ), B-cell lymphopenia (including B cells ≤1%; switched memory B cells ≤2% of the total B cells; low SARS-CoV-2-specific memory B cells) ( 20 , 22 , 23 , 115 , 117 , 118 , 121 – 123 ), low levels of IgA and IgM ( 22 , 121 ), and T-cell lymphopenia ( 20 ) with reduced T-memory activation ( 123 ).…”