Binding dynamics shape germinal center broadly neutralizing responses to HIV priming

Area of Science:

• Immunology
• Vaccinology
• Structural Biology

Background:

• Inducing broadly neutralizing antibodies (bnAbs) is crucial for effective HIV vaccines.
• bnAb precursors are rare and require extensive somatic hypermutation (SHM) for epitope recognition.
• Germline-targeting immunogens (GTs) aim to initiate bnAb development, but their success factors are not fully understood.

Purpose of the Study:

• To identify key determinants of success for germline-targeting immunogens (GTs) in initiating broadly neutralizing antibody (bnAb) precursor development.
• To establish a model system for tracking bnAb precursors and evaluating immunogen performance.

Main Methods:

• Development of a bnAb precursor-trackable model.
• Testing a series of GTs with varying binding dynamics.
• Analysis of germinal center fitness and somatic hypermutation (SHM) pathways.
• Single-cell transcriptomics to identify predictive gene programs.

Main Results:

• Multivalent GT designs that engage B-cells transiently, rather than tightly, consistently outperformed others.
• Transient engagement boosted germinal center fitness and facilitated efficient SHM pathways for breadth.
• These effects were independent of antibody affinity or precursor frequency.
• Single-cell transcriptomics identified gene programs associated with successful B-cell priming.

Conclusions:

• Binding dynamics, specifically transient B-cell engagement, are a critical, previously unrecognized driver of successful bnAb precursor development.
• This scalable system offers predictive power for immunogen performance in HIV vaccine development.
• The findings may provide a broadly applicable framework for streamlining pre-clinical pipelines, including immunogenicity and safety assessments for various vaccines.