Optimal Sequential Immunization Can Focus Antibody Responses against Diversity Loss and Distraction

Area of Science:

• Immunology
• Computational Biology
• Vaccinology

Background:

• Affinity maturation is key for potent antibody evolution and immune memory.
• Complex pathogens with diverse antigens challenge natural immunity and vaccine design.
• Inducing broadly neutralizing antibodies (bnAbs) requires understanding B cell responses to varied antigens.

Purpose of the Study:

• To model affinity maturation under conditions relevant to vaccine development.
• To investigate the impact of reduced B cell diversity and distracting epitopes on antibody breadth.
• To explore how temporal immunization patterns influence B cell evolution and bnAb induction.

Main Methods:

• Developed an in silico model of B lymphocyte affinity maturation.
• Simulated successive immunizations with distinct antigen variants.
• Analyzed the effects of B cell diversity loss and epitope distraction on antibody responses.

Main Results:

• B cell diversity loss and distracting epitopes significantly impact antibody breadth.
• The temporal pattern of immunization critically influences evolutionary outcomes.
• Sequential immunization with distant variants robustly induces bnAbs targeting conserved epitopes.
• Antigenic history shapes B cell lineage evolution and antibody response modes.

Conclusions:

• Vaccine design can be guided by understanding how selection pressures and immunization timing affect antibody breadth.
• Sequential immunization strategies may be optimal for inducing broadly neutralizing antibodies against mutating pathogens.
• Optimal antigen dosing is crucial for balancing adaptation and persistent immune reactions.