Phased fragility and stability of non-genetic B cell states in the germinal center accelerate the genetic evolution of antibodies

Vaccine responses depend on the Darwinian genetic evolution of B cells to generate high-affinity antibodies. However, B cells gain non-genetic heterogeneity while searching for antigen and T helper cells, but then their non-genetic cell states remain stable within proliferative clonal bursts. We explored the functional consequence of this dynamic control of non-genetic variability by developing a mathematical model, integrating a wealth of immunological knowledge. We discovered that variability in B cell fate decisions does not impair but instead accelerates affinity maturation by allowing high-affinity outliers to escape plasma cell differentiation and seed further rounds of Darwinian evolution. During clonal bursts, non-genetic cell state stability further promotes their amplification. The resulting model correctly predicts emergent vaccine response properties in mouse strains with altered B cell fate decision profiles. Our work reconciles classical B cell clonal selection theory with the experimentally observed non-genetic variability, and it provides an interpretable knowledge-based modeling framework to support personalized vaccination strategies.