Class-switched CD21 + CD27 + memory B cells as a predictive immunological marker of vaccine-induced humoral responsiveness in Common Variable Immunodeficiency

Common variable immunodeficiency (CVID) is a clinically heterogeneous primary immunodeficiency characterized by defective humoral immunity and highly variable vaccine-induced antibody responses. However, in-depth characterization of vaccine-specific B cell responses in CVID remains limited, hindering our understanding of the cellular basis of this heterogeneity. Here, we investigated how CVID affects formation and maintenance of antigen-specific B cell responses following COVID-19 mRNA-based vaccination of patients who either do (responders; R) or do not (non-responders; NR) seroconvert. The evolution of the spike (S)-specific B cell compartment was longitudinally investigated after vaccination and compared to RSV-F-specific B cells, as a historically encountered antigen, and the total B cell compartment. CVID-NR patients showed pronouncedly reduced S-specific B cell numbers at all time points compared to CVID-R and healthy donors. Additionally, the S-specific B cell compartment showed a predominantly naïve, unswitched phenotype. CVID-R exhibited a delayed S-specific B cell differentiation, with a markedly naïve, unswitched response after the first vaccination, an enhanced response after the second vaccination with reduced IgG⁺ memory B cells, and a fully established S-specific B cell compartment 6 months after vaccination. Analysis of the general B cell compartment showed strongly diminished class-switched B cell populations in NR patients, emerging as a predictive immunological marker for vaccine-induced humoral responsiveness in CVID. Together, these findings reveal distinct cellular alterations underlying vaccine responsiveness in patients with CVID and identify potential correlates of humoral vaccine responses, stablishing a framework for more personalized immune monitoring strategies in CVID.