Defining Clinical and Immunological Predictors of Poor Immune Responses to COVID-19 mRNA Vaccines in Patients with Primary Antibody Deficiency

Abstract

Immune responses to coronavirus disease 2019 (COVID-19) mRNA vaccines in primary antibody deficiencies (PADs) are largely unknown. We investigated antibody and CD4 + T-cell responses specific for SARS-CoV-2 spike protein (S) before and after vaccination and associations between vaccine response and patients' clinical and immunological characteristics in PADs. The PAD cohort consisted of common variable immune deficiency (CVID) and other PADs, not meeting the criteria for CVID diagnosis (oPADs). Anti-S IgG, IgA, and IgG subclasses 1 and 3 increased after vaccination and correlated with neutralization activity in HCs and patients with oPADs. However, 42% of CVID patients developed such responses after the 2nd dose. A similar pattern was also observed with S-specific CD4 + T-cells as determined by OX40 and 4-1BB expression. Patients with poor anti-S IgG response had significantly lower levels of baseline IgG, IgA, CD19 + B-cells, switched memory B-cells, naïve CD8 + T-cells, and a higher frequency of EM CD8 + T-cells and autoimmunity compared to patients with adequate anti-S IgG responses. Patients with oPADs can develop humoral and cellular immune responses to vaccines similar to HCs. However, a subset of CVID patients exhibit impairment in developing such responses, which can be predicted by the baseline immune profile and history of autoimmunity.

Long-Term Immunological Memory of SARS-CoV-2 Is Present in Patients with Primary Antibody Deficiencies for up to a Year after Vaccination

“…The results are consistent with a previously reported expansion of the T-cell memory subsets in patients with IEI and healthy controls 28 days after vaccination with the BNT162b2 mRNA vaccine [ 28 ]. However, a recent study examining immunological predictors of impaired immune response to SARS-CoV-2 vaccination found no association to central memory CD4+ or CD8+ T cells, but a significantly higher frequency of effector memory CD8+ T cells in those of impaired humoral immune response [ 36 ], and a similar trend has also been observed with humoral response to influenzae vaccination in CVID patients [ 55 ]. We found no significant relationship between long-term anti-spike humoral response and B-cell subsets, consistent with reports on early vaccination responses in IEI patients where there was no variation in the B-cell compartment a month after vaccination was reported [ 28 ].…”

“…Primary antibody deficiency patients with a history of autoimmunity have previously been reported to have a poorer response to vaccination [ 36 ]. In this study, we were not able to identify an association between the magnitude of the immune response and clinical manifestations.…”

“…We found no significant relationship between long-term anti-spike humoral response and B-cell subsets, consistent with reports on early vaccination responses in IEI patients where there was no variation in the B-cell compartment a month after vaccination was reported [ 28 ]. However, in PAD patients, lower levels of baseline IgG, IgA, total B cells, and switched memory B cells were related to poor SARS-CoV-2 vaccine anti-spike antibody response [ 36 ]. In addition, following influenza vaccination, in patients with CVID, numbers of circulating switched memory B lymphocytes (EUROClass B+ smB+) were directly correlated with a superior humoral immune response [ 56 ].…”

“…In addition, no study to date has investigated the humoral and cellular immune response to SARS-CoV-2 vaccination, specifically in sIgAD patients. In addition, only a few studies have explored immunological correlations and predictive markers associated with higher immune responses after SARS-CoV-2 vaccination, most of them evaluating early immune responses [ 28 , 33 , 34 , 35 , 36 ].…”

Impaired B Cell Recall Memory and Reduced Antibody Avidity but Robust T Cell Response in CVID Patients After COVID-19 Vaccination

“…More importantly, the detection of specific antibodies after COVID-19 vaccination raises important questions on the quality and longevity of the humoral immune response, since the seroconversion state has potential clinical implications for treatment in SARS-CoV-2-infected CVID patients. Functional assessments of humoral immunity already revealed that CVID patients express lower neutralizing antibody levels than healthy individuals [ 8 – 11 , 15 ]. Avidity of generated antibodies was analyzed in two recent studies, reporting similar levels of antibody avidity in CVID patients and healthy individuals 4 weeks after second COVID-19 vaccination but without significant increase after more than two vaccinations [ 9 , 16 ].…”