Binding dynamics shape germinal center broadly neutralizing responses to HIV priming

SUMMARY Inducing broadly neutralizing antibodies (bnAbs) is central to HIV vaccine efforts, but bnAb precursors are rare, often inactive, and require extensive somatic hypermutation (SHM) to recognize diverse, glycan-shielded epitopes. Germline-targeting immunogens (GTs) aim to jump-start this process, but determinants of success remain unclear. Here we establish a bnAb precursor-trackable model that reveals a surprising driver: binding dynamics. Across a series of GTs, multivalent designs that engage B-cells transiently - not tightly - consistently outperformed others, boosting germinal center fitness and unlocking rare or more efficient SHM pathways for breadth. These effects were independent of affinity or precursor frequency. Single-cell transcriptomics uncovered gene programs that predict successful priming. Crucially, this scalable system provides general predictive power for immunogen performance, marking a major advance for not only HIV vaccine development, but also potentially establishing a broadly applicable framework for streamlining pre-clinical pipelines, including immunogenicity and safety evaluation.