{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T06:09:07Z","timestamp":1789711747702,"version":"4.0.1"},"reference-count":80,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T00:00:00Z","timestamp":1789689600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100016302","name":"Coalition for Epidemic Preparedness Innovations","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100016302","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>The rapid evolution of SARS-CoV-2 and the ongoing risk of zoonotic spillover highlight the need for vaccines that provide broad protection beyond strain-specific immunity. Here, we present a structure-guided, AI-enabled strategy for rational antigen design that enhances cross-reactive B-cell epitope recognition across betacoronaviruses. By integrating comparative sequence analysis with conformational epitope prediction, we identified conserved epitope hotspots within the Spike receptor-binding domain and introduced targeted motif-level substitutions into a SARS-CoV-2 BA.2 backbone. Engineered Spike immunogens, delivered as mRNA-lipid nanoparticle vaccines, elicited robust antibody responses in mice and demonstrated broad neutralizing activity against antigenically diverse SARS-CoV-2 variants, including BA.5 and XBB.1.5, as well as zoonotic sarbecoviruses. Selected designs reached neutralisation breadth comparable to an Omicron-adapted clinical benchmark for shared SARS-CoV-2 antigens, while extending neutralising activity to divergent zoonotic sarbecoviruses. These findings show that minimal, structure-guided epitope remodeling can enhance the presentation of conserved epitopes and improve antibody breadth, providing a generalizable framework for designing vaccines resilient to viral evolution and future pandemic threats.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1919664","type":"journal-article","created":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T05:39:16Z","timestamp":1789709956000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["AI-guided epitope engineering of a SARS-CoV-2 spike antigen for broad sarbecovirus neutralization"],"prefix":"10.3389","volume":"17","author":[{"given":"Alexandru","family":"Odainic","sequence":"first","affiliation":[{"name":"NEC Bio B.V.","place":["Amsterdam, Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ioannis","family":"Vardaxis","sequence":"additional","affiliation":[{"name":"NEC Bio 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