BAFF-R Expression as a Potential Biomarker Associated with COVID-19 Vaccine Non-Responsiveness in Antibody-Deficient Patients

INTRODUCTION: Patients with primary and secondary antibody deficiencies exhibit variable responses to vaccination, with many failing to mount optimal immunity to SARS-CoV-2. Mechanisms underpinning vaccine non-responsiveness remain poorly defined and unpredictable. We hypothesised that B-cell-intrinsic features are associated with SARS-CoV-2 vaccine failure. METHODS: Peripheral B-cells from 49 patients enrolled in the COVID-19 in Antibody Deficiency (COV-AD) study underwent a validated in vitro B-cell differentiation assay. We assessed plasmablast and plasma cell (PC) generation, immunoglobulin production, immunoglobulin heavy chain (IGH) repertoire diversity, and BAFF-R expression. RESULTS: Vaccine non-responders displayed reduced IgA class-switched immunoglobulin production in vitro compared to healthy controls and responders. Moreover, while the relative percentage of PC output was comparable between groups, the overall number of cells obtained from non-responders was reduced. Most non-responders and a subset of responders exhibited reduced BAFF-R surface expression at baseline compared to healthy controls, though with considerable overlap between groups. BAFF-R transcript levels partially corresponded with surface expression but varied and did not clearly distinguish response. No compensatory upregulation of alternative BAFF receptors or elevated serum BAFF was observed. IGH repertoire analysis revealed preserved diversity among patients. CONCLUSIONS: Diminished BAFF-R expression is associated with vaccine non-responsiveness and may indicate underlying B-cell-intrinsic defects. BAFF-R shows potential as a candidate biomarker that merits further validation in larger, multicentre cohorts to determine its clinical utility for stratifying patients at risk of vaccine failure. These findings suggest that the BAFF/BAFF-R axis may play an important role in vaccine-induced humoral immunity in antibody-deficient patients, warranting further mechanistic investigation.