{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T04:49:04Z","timestamp":1789447744095,"version":"build-2803163510"},"update-to":[{"DOI":"10.1371\/journal.ppat.1013905","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T00:00:00Z","timestamp":1777248000000}}],"reference-count":82,"publisher":"Public Library of Science (PLoS)","issue":"2","license":[{"start":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T00:00:00Z","timestamp":1771459200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006800","name":"Honorable Tina Brozman Foundation","doi-asserted-by":"publisher","award":["RSG2-22-23"],"award-info":[{"award-number":["RSG2-22-23"]}],"id":[{"id":"10.13039\/100006800","id-type":"DOI","asserted-by":"publisher"}]},{"name":"NIH","award":["AI165066"],"award-info":[{"award-number":["AI165066"]}]},{"name":"NIH","award":["CA009171"],"award-info":[{"award-number":["CA009171"]}]},{"name":"NIH","award":["75N93019C0005"],"award-info":[{"award-number":["75N93019C0005"]}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>New SARS-CoV-2 variants pose an ongoing threat due to persistent immune escape of natural and vaccine-induced immunity. The emergence of BA.1 (Omicron) produced a large antigenic shift in the spike protein, rendering many antibodies ineffective with concomitant loss of Emergency Use Authorization (EUA) status. While strains have evolved far from BA.1, re-emergence of variants from branches closer to BA.1 are of recent concern. Here, we engineered a self-assembling nanoparticle displaying RBD 4mut g5.1, an immunogen developed using structure-guided design to focus antibody responses to the receptor binding site (RBS) epitope and promote cross-reactivity by inclusion of four rationally selected BA.1 mutations in the RBS. Unlike multi-component RBD approaches, we demonstrate a single, rationally designed component is sufficient for generating broad immunity. We demonstrate that in both na\u00efve and antigen-experienced mice, RBD 4mut g5.1 nanoparticle induced cross-reactive and durable antibody responses capable of potent neutralization of ancestral SARS-CoV-2 and many Omicron variants. RBD 4mut g5.1 provided heterologous protection at a memory timepoint. By showcasing how subtle changes in an epitope can trigger a diversified antibody response, this study offers a promising new avenue for developing vaccines that can more effectively tackle the ever-evolving threat of immune escape, not only against SARS-CoV-2 but potentially against a range of variable pathogens.<\/jats:p>","DOI":"10.1371\/journal.ppat.1013905","type":"journal-article","created":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T18:41:54Z","timestamp":1771526514000},"page":"e1013905","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Immune-focused RBD nanoparticles induce cross-reactive, RBS-directed responses capable of variant-resistant SARS-CoV-2 neutralization"],"prefix":"10.1371","volume":"22","author":[{"given":"Kylie M.","family":"Konrath","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Liaw","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas J.","family":"Tursi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madison E.","family":"McCanna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryce M.","family":"Warner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ebony 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R.F.","family":"Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darwyn","family":"Kobasa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David B.","family":"Weiner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0527-3804","authenticated-orcid":true,"given":"Daniel W.","family":"Kulp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,2,19]]},"reference":[{"key":"ppat.1013905.ref001","unstructured":"World Health Organization. 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Historical working definitions and primary actions for SARS-CoV-2 variants. 2023."},{"key":"ppat.1013905.ref015","unstructured":"CoVariants. https:\/\/covariants.org\/variants. Accessed 2024 February 20."},{"key":"ppat.1013905.ref016","doi-asserted-by":"crossref","first-page":"940956","DOI":"10.3389\/fpubh.2022.940956","article-title":"The Vaccine Efficacy Against the SARS-CoV-2 Omicron: A Systemic Review and Meta-Analysis","volume":"10","author":"Y Zou","year":"2022","journal-title":"Front Public Health"},{"issue":"4","key":"ppat.1013905.ref017","doi-asserted-by":"crossref","first-page":"1024","DOI":"10.1016\/j.cell.2020.09.037","article-title":"Mapping Neutralizing and Immunodominant Sites on the SARS-CoV-2 Spike Receptor-Binding Domain by Structure-Guided High-Resolution Serology","volume":"183","author":"L Piccoli","year":"2020","journal-title":"Cell"},{"issue":"7839","key":"ppat.1013905.ref018","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1038\/s41586-020-2852-1","article-title":"SARS-CoV-2 neutralizing antibody structures inform therapeutic strategies","volume":"588","author":"CO 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Yisimayi","year":"2024","journal-title":"Nature"},{"issue":"6530","key":"ppat.1013905.ref025","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1126\/science.abf6840","article-title":"Mosaic nanoparticles elicit cross-reactive immune responses to zoonotic coronaviruses in mice","volume":"371","author":"AA Cohen","year":"2021","journal-title":"Science"},{"issue":"12","key":"ppat.1013905.ref026","doi-asserted-by":"crossref","first-page":"2419","DOI":"10.1016\/j.immuni.2022.10.019","article-title":"Neutralizing monoclonal antibodies elicited by mosaic RBD nanoparticles bind conserved sarbecovirus epitopes","volume":"55","author":"C Fan","year":"2022","journal-title":"Immunity"},{"key":"ppat.1013905.ref027","article-title":"Designed mosaic nanoparticles enhance cross-reactive immune responses in mice","author":"E Wang","year":"2024","journal-title":"bioRxiv"},{"issue":"27","key":"ppat.1013905.ref028","article-title":"A Mosaic Nanoparticle Vaccine Elicits Potent Mucosal Immune Response with Significant Cross-Protection Activity against Multiple SARS-CoV-2 Sublineages","volume":"10","author":"X Zhang","year":"2023","journal-title":"Adv Sci (Weinh)"},{"issue":"12","key":"ppat.1013905.ref029","doi-asserted-by":"crossref","first-page":"105649","DOI":"10.1016\/j.isci.2022.105649","article-title":"Co-display of diverse spike proteins on nanoparticles broadens sarbecovirus neutralizing antibody responses","volume":"25","author":"M Brinkkemper","year":"2022","journal-title":"iScience"},{"issue":"8","key":"ppat.1013905.ref030","doi-asserted-by":"crossref","first-page":"1501","DOI":"10.1016\/j.immuni.2022.06.005","article-title":"Atlas of currently available human neutralizing antibodies against SARS-CoV-2 and escape by Omicron sub-variants BA.1\/BA.1.1\/BA.2\/BA.3","volume":"55","author":"M Huang","year":"2022","journal-title":"Immunity"},{"issue":"5","key":"ppat.1013905.ref031","doi-asserted-by":"crossref","first-page":"110318","DOI":"10.1016\/j.celrep.2022.110318","article-title":"Nucleic acid delivery of immune-focused SARS-CoV-2 nanoparticles drives rapid and potent immunogenicity capable of single-dose protection","volume":"38","author":"KM Konrath","year":"2022","journal-title":"Cell Rep"},{"issue":"9","key":"ppat.1013905.ref032","doi-asserted-by":"crossref","first-page":"2384","DOI":"10.1016\/j.cell.2021.03.036","article-title":"SARS-CoV-2 variants B.1.351 and P.1 escape from neutralizing antibodies","volume":"184","author":"M Hoffmann","year":"2021","journal-title":"Cell"},{"issue":"9","key":"ppat.1013905.ref033","doi-asserted-by":"crossref","first-page":"2348","DOI":"10.1016\/j.cell.2021.02.037","article-title":"Evidence of escape of SARS-CoV-2 variant B.1.351 from natural and vaccine-induced sera","volume":"184","author":"D Zhou","year":"2021","journal-title":"Cell"},{"issue":"7857","key":"ppat.1013905.ref034","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1038\/s41586-021-03398-2","article-title":"Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7","volume":"593","author":"P Wang","year":"2021","journal-title":"Nature"},{"issue":"20","key":"ppat.1013905.ref035","doi-asserted-by":"crossref","first-page":"3292","DOI":"10.1016\/j.vaccine.2023.03.069","article-title":"Vaccine effectiveness against transmission of alpha, delta and omicron SARS-COV-2-infection, Belgian contact tracing, 2021-2022","volume":"41","author":"T Braeye","year":"2023","journal-title":"Vaccine"},{"issue":"6581","key":"ppat.1013905.ref036","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1126\/science.abn7591","article-title":"Neutralization of SARS-CoV-2 Omicron by BNT162b2 mRNA vaccine-elicited human sera","volume":"375","author":"A 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Rep"},{"issue":"6","key":"ppat.1013905.ref040","doi-asserted-by":"crossref","first-page":"206","DOI":"10.15585\/mmwr.mm7106a4","article-title":"Genomic Surveillance for SARS-CoV-2 Variants: Predominance of the Delta (B.1.617.2) and Omicron (B.1.1.529) Variants - United States, June 2021-January 2022","volume":"71","author":"AS Lambrou","year":"2022","journal-title":"MMWR Morb Mortal Wkly Rep"},{"issue":"23","key":"ppat.1013905.ref041","doi-asserted-by":"crossref","first-page":"846","DOI":"10.15585\/mmwr.mm7023a3","article-title":"Genomic Surveillance for SARS-CoV-2 Variants Circulating in the United States, December 2020-May 2021","volume":"70","author":"P Paul","year":"2021","journal-title":"MMWR Morb Mortal Wkly Rep"},{"issue":"8","key":"ppat.1013905.ref042","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.1038\/s41564-022-01143-7","article-title":"SARS-CoV-2 Omicron is an immune escape variant with an altered cell entry pathway","volume":"7","author":"BJ 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Wang","year":"2021","journal-title":"Science"},{"issue":"4","key":"ppat.1013905.ref049","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1016\/j.cell.2020.09.035","article-title":"Structurally Resolved SARS-CoV-2 Antibody Shows High Efficacy in Severely Infected Hamsters and Provides a Potent Cocktail Pairing Strategy","volume":"183","author":"S Du","year":"2020","journal-title":"Cell"},{"issue":"6579","key":"ppat.1013905.ref050","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1126\/science.abm8143","article-title":"Antibody-mediated broad sarbecovirus neutralization through ACE2 molecular mimicry","volume":"375","author":"Y-J Park","year":"2022","journal-title":"Science"},{"issue":"1","key":"ppat.1013905.ref051","doi-asserted-by":"crossref","first-page":"3537","DOI":"10.1038\/s41467-023-39267-x","article-title":"Discovery and characterization of potent pan-variant SARS-CoV-2 neutralizing antibodies from individuals with Omicron breakthrough 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