In our study impaired activation of CXCR5-negative CD4+ memory cells but not cTfh characterized IgG nonresponsiveness in patients with CVID, while antigen-specific activation of CXCR5-positive cTfh was comparably reduced in CVID BNT162b2-IgG-responders and nonresponders. This evidence concerns the gene CD4 and common variable immunodeficiency.