Work

Binding dynamics shape germinal center broadly neutralizing responses to HIV priming

Year: 2026

Type: preprint

Abstract: 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.

Source: Research Square

DOI: 10.21203/rs.3.rs-9368628/v1