Iyaniwura, S. A.; Mayer, B. T.; Hahn, W.; Kim, S.-Y.; Huang, Y.; Hyrien, O.

Vaccine-induced humoral immunity emerges from complex interactions among competing B-cell populations and antibody production in response to antigen exposure, yet the mechanisms governing these interactions remain only partially understood. We developed a mechanistic mathematical model that integrates vaccine regimen features, immunogen kinetics, multiclass B-cell dynamics, and germinal center processes. The model was calibrated to data from the G001 HIV vaccine trial evaluating eOD-GT8, a germline-targeting immunogen designed to activate VRC01-class precursor B cells capable of developing into broadly neutralizing antibody-producing cells. The model reproduced key features of the observed B-cell and antibody responses, enabled estimation of class-specific activation and competition parameters, and supported investigation of the identifiability of competition parameters. Activation rates varied across B-cell classes, with memory B cells exhibiting substantially higher activation rates than naive B cells. Importantly, competition was stronger within than between classes, with the strongest competition occurring among VRC01-class B cells. These findings suggest that class-specific differences in activation and competition shape the magnitude and composition of vaccine-induced humoral response and may influence the expansion of broadly neutralizing antibody precursors. More broadly, the model provides a quantitative framework for dissecting multiclass B-cell competition and antibody responses, and for evaluating how vaccination strategies shape humoral immunity.