Simon Lab (@vivianasimonlab.bsky.social)

Convergent and clonotype-enriched mutations in the light chain drive affinity maturation of a public antibody 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 IGHV4-59/IGKV3-20 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. ### Competing Interest Statement The Icahn School of Medicine at Mount Sinai has submitted patent applications related to SARS-CoV-2 serological assays, NDV-based SARS-CoV-2 vaccines, influenza virus vaccines, and influenza virus therapeutics, with Florian Krammer listed as a co-inventor. Viviana Simon is named as a co-inventor on the SARS-CoV-2 serological assay patent application. Mount Sinai has established a company, Kantaro, to commercialize serological tests for SARS-CoV-2, and another company, CastleVax, to develop SARS-CoV-2 vaccines. Florian Krammer is a co-founder and serves on the scientific advisory board of CastleVax. He has provided consulting services to Merck, Curevac, GSK, Seqirus, and Pfizer and is currently advising 3rd Rock Ventures, Gritstone, and Avimex. Additionally, the Krammer laboratory is collaborating with Dynavax on influenza vaccine development and with VIR on influenza virus therapeutics. The Wesemann laboratory receives grants from Sanofi and Merk for antibody and technology studies. https://www.biorxiv.org/content/10.1101/2025.03.07.642041v1