Engineering an Antibody V Gene-Selective Vaccine.

Area of Science:

• Immunology
• Vaccinology
• Structural Biology

Background:

• The B cell receptor (BCR) surface is critical for antigen recognition, involving encoded and non-encoded complementarity determining regions (CDRs).
• Genetically reproducible antibodies, particularly broadly neutralizing ones against HIV and influenza, arise when encoded CDRs dictate antigen recognition.
• Engineering vaccines to target specific BCR configurations could enable precise immune responses.

Purpose of the Study:

• To develop a method for engineering virus-like-particle (VLP) vaccines that target specific gene-encoded moieties of the BCR antigen binding site.
• To identify a multivalent antigen capable of selectively triggering germline BCRs, specifically those utilizing the human V_H gene IGVH1-2*02.
• To demonstrate a proof-of-concept for generating antigens that engage predefined BCR configurations without prior structure-based information.

Main Methods:

• Deployment of a library of RNA bacteriophage VLPs displaying random peptides.
• Screening for VLPs that exhibit multivalent affinity for gene-encoded BCR elements.
• Utilizing humanized mice with diverse germline antibody repertoires to test VLP-mediated BCR priming.

Main Results:

• Identification of a specific multivalent antigen displayed on VLPs.
• Demonstration that this VLP selectively triggered germline BCRs expressing the IGHV1-2*02 gene.
• Successful priming of specific BCR configurations within a highly diversified repertoire in humanized mice.

Conclusions:

• The developed VLP-based approach provides a methodology to generate antigens that engage specific BCR configurations.
• This strategy enables the targeting of particular BCRs of interest, even without detailed structural information.
• The findings offer a novel platform for vaccine design, potentially leading to more targeted and effective immunotherapies.