Modelling plasma cell differentiation to risk stratify secondary antibody deficiencies for immunoglobulin replacement therapy

B-cells of patients with secondary and primary antibody deficiency often exhibit
defects in maturation, activation, or survival, which may lead to impaired immune
responses after SARS-CoV-2 vaccination. These defects contribute to vaccine non-
responsiveness in some patients. The underlying mechanisms and the feasibility of
pre-vaccination risk stratification remain unclear. To investigate B-cell intrinsic
differentiation capacities in a heterogeneous cohort of vaccine-responding and non-
responding antibody-deficient patients, an in vitro plasma cell differentiation model
has been utilised. Such an approach may also be useful in assessing their suitability
for immunoglobulin replacement therapy (IgRT).
B-cells from participants enrolled in the COV-AD study, taken after their fourth
SARS-CoV-2 vaccine dose, were isolated and induced to differentiate into plasma
cells. B-cell functionality at critical differentiation stages was assessed using flow
cytometry, ELISA, BCR analysis, and RNA sequencing. The study revealed distinct
differences in B-cell differentiation between vaccine responders and non-responders.
Non-responders (n=15) and a subset of responders (n=10/35) exhibited significantly
reduced or absent expression of the BAFF-R survival receptor. Immunoglobulin
heavy chain sequencing showed no significant differences in BCR profiles between
responders and non-responders. Both patient groups displayed reduced intracellular
and secreted IgG and IgA expression compared to healthy controls.
Atypical B-cell differentiation profiles in antibody deficient patients, particularly
reduced BAFF-R expression, may underpin impaired SARS-CoV-2 vaccine
responses. The identification of BAFF-R as a critical survival receptor emphasises its
potential as a biomarker for risk stratification. Integrating BAFF-R profiling into
clinical workflows could help identify patients at risk of poor immune outcomes,
enabling tailored therapeutic interventions. Refining this in vitro plasma cell
differentiation model to allow for faster assessments, focusing on BAFF-R levels and
other key markers, will enhance its feasibility as a practical tool for pre-IgRT risk
stratification in clinical settings.