Convergent and clonotype-enriched mutations in the light chain drive affinity maturation of a public antibody.

bioRxiv : the preprint server for biology
Authors
Keywords
Abstract

Public antibodies that recognize conserved epitopes are critical for vaccine development, and identifying somatic hypermutations (SHMs) that enhance antigen affinity in these public responses is key to guiding vaccine design for better protection. We propose that affinity-enhancing SHMs are selectively enriched in public antibody clonotypes, surpassing the background frequency seen in antibodies carrying the same V genes, but with different epitope specificities. Employing a human / public antibody as a model, we compare SHM signatures in antibodies also using these V genes, but recognizing other epitopes. Critically, this comparison identified clonotype-enriched mutations in the light chain. Our analyses also show that these SHMs, in combination, enhance binding to a previously uncharacterized viral epitope, with antibody responses to it increasing after multiple vaccinations. Our findings offer a framework for identifying affinity-enhancing SHMs in public antibodies based on convergence and clonotype-enrichment and can help guide vaccine design aimed to elicit public antibodies.

Year of Publication
2025
Journal
bioRxiv : the preprint server for biology
Date Published
03/2025
ISSN
2692-8205
DOI
10.1101/2025.03.07.642041
PubMed ID
40161664
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