A paradigm shift in simulating affinity maturation to elicit broadly neutralizing antibodies

Area of Science:

• Immunology
• Molecular Biology
• Vaccinology

Background:

• Broadly neutralizing antibodies (bnAbs) are key to combating rapidly evolving pathogens like HIV, influenza, and SARS-CoV-2.
• Eliciting bnAbs through vaccination is challenging, with antibody affinity maturation (AM) in germinal centers (GCs) being a critical process.
• Traditional models view AM as solely driven by high-affinity B cell receptor (BCR) selection, potentially limiting diversity.

Purpose of the Study:

• To reassess traditional affinity-based selection models of AM.
• To propose a new paradigm integrating multifactorial processes in AM.
• To advance strategies for developing effective vaccines against mutable pathogens.

Main Methods:

• Review and reevaluation of existing affinity-based selection models for AM.
• Integration of emerging evidence on GC permissiveness and B cell diversity.
• Incorporation of stochastic B cell dynamics, antigen extraction efficiency, and avidity effects.
• Highlighting advanced AM simulations beyond single-affinity determinants.

Main Results:

• Emerging evidence suggests GCs are permissive, allowing diverse B cell affinities to persist.
• A new paradigm integrates stochasticity, antigen binding dynamics, and avidity.
• Advanced simulations offer more realistic AM representations.

Conclusions:

• Antibody affinity maturation is a multifactorial process, not solely driven by affinity.
• A revised understanding of AM is essential for designing effective vaccines against complex, mutable antigens.
• This work provides a framework for developing improved vaccine strategies to elicit bnAbs.