B-Cell Remodeling and Regulatory Phenotypes During Acute COVID-19 Are Unaffected by Polyclonal Anti-SARS-CoV-2 Antibody XAV-19.

Regulatory B cells (Bregs) are emerging as pivotal modulators of immune balance, yet their dynamics during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and their response to passive antibody therapy remain largely unexplored. In the immunological sub-study of the randomized, placebo-controlled POLYCOR trial evaluating XAV-19, a glyco-humanized polyclonal anti-SARS-CoV-2 antibody, we performed longitudinal immune profiling of hospitalized COVID-19 patients using spectral flow cytometry, in vitro functional assays, and single-cell RNA sequencing. SARS-CoV-2 infection triggered a transient remodeling of the B-cell compartment, with expansion of activated B cells and plasmablasts, contraction of switched memory B cells, and enrichment of B cells expressing regulatory-associated markers, including PD-L1, CD9, granzyme B, and IL-10. Transcriptional analyses revealed dynamic reprogramming, characterized by downregulation of adhesion and costimulatory genes (CD27, ITGB7) and emergence of an interferon-driven memory B-cell signature (SOCS1, IFI27). In contrast, XAV-19 treatment preserved B-cell homeostasis, showing minimal impact on phenotype, function, and gene expression. Together, these findings uncover a transient regulatory adaptation of B cells during acute COVID-19 and demonstrate that XAV-19 therapy maintains immune equilibrium, reinforcing its safety and supporting the concept of immunologically neutral passive antibody therapy.