{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T19:42:05Z","timestamp":1792093325358,"version":"4.4.0"},"reference-count":80,"publisher":"eLife Sciences Publications, Ltd","license":[{"start":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T00:00:00Z","timestamp":1777507200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T00:00:00Z","timestamp":1777507200000},"content-version":"am","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T00:00:00Z","timestamp":1777507200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["P01-AI165075"],"award-info":[{"award-number":["P01-AI165075"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"award":["P01-AI165075"],"award-info":[{"award-number":["P01-AI165075"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["DP5OD033362"],"award-info":[{"award-number":["DP5OD033362"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"award":["DP5OD033362"],"award-info":[{"award-number":["DP5OD033362"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Gates Foundation","award":["INV-034638"],"award-info":[{"award-number":["INV-034638"]}]},{"award":["INV-034638"],"award-info":[{"award-number":["INV-034638"]}],"id":[{"id":"https:\/\/ror.org\/0456r8d26","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Gates Foundation","award":["INV-056219"],"award-info":[{"award-number":["INV-056219"]}]},{"award":["INV-056219"],"award-info":[{"award-number":["INV-056219"]}],"id":[{"id":"https:\/\/ror.org\/0456r8d26","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100023001","name":"Merkin Institute for Translational Research, California Institute of Technology","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100023001","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/05dxps055","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006369","name":"George Mason University","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100006369","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/02jqj7156","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100028897","name":"Wellcome Leap","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100028897","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/029chgv08","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":["elifesciences.org"],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>mRNA vaccines emerged as a leading vaccine technology during the COVID-19 pandemic. However, their sustained protective efficacies were limited by relatively short-lived antibody responses and the emergence of SARS-CoV-2 variants, necessitating frequent and variant-updated boosters. We recently developed the ESCRT- and ALIX-binding region (EABR) mRNA vaccine platform, which encodes engineered immunogens that induce budding of enveloped virus-like particles (eVLPs) from the plasma membrane, thereby resulting in presentation of immunogens on cell surfaces and eVLPs. Prior studies showed that spike (S)-EABR mRNA-LNP immunizations elicited enhanced neutralizing antibody responses against ancestral and variant SARS-CoV-2 compared with conventional S mRNA-LNP in na\u00efve mice, but the effectiveness of S-EABR mRNA-LNP boosters in the context of pre-existing immunity has not been investigated. Here, we evaluated monovalent Wuhan-Hu-1 (Wu1) and bivalent (Wu1\/BA.5) S-EABR mRNA-LNP boosters in mice pre-vaccinated with conventional Wu1 S mRNA-LNP. Compared to conventional S mRNA-LNP boosters, the EABR approach enhanced monovalent and bivalent mRNA-LNP booster-induced neutralizing responses against Omicron subvariants BA.1, BA.5, BQ.1.1, and XBB.1, with bivalent S-EABR mRNA-LNP consistently eliciting the highest titers. Epitope mapping of polyclonal antisera by deep mutational scanning revealed that bivalent S-EABR mRNA-LNP boosted diverse \u2018polyclass\u2019 anti-receptor-binding domain (RBD) responses, suggesting balanced targeting of multiple RBD epitope classes. In contrast, monovalent S, bivalent S, and monovalent S-EABR mRNA-LNP boosters elicited less diverse polyclonal serum responses primarily targeting immunodominant RBD epitopes. Cryo-electron microscopy (cryo-EM) structures demonstrated that bivalent mRNA immunizations promote S heterotrimer formation, potentially enhancing bivalent S-EABR mRNA-LNP booster-induced antibody breadth and polyclass epitope targeting by activating cross-reactive B cells through intra-S crosslinking. These findings support the future design of bivalent or multivalent S-EABR mRNA-LNP boosters as a promising strategy to confer broader, and therefore potentially more durable, protection against emerging SARS-CoV-2 variants and other rapidly evolving viruses.<\/jats:p>","DOI":"10.7554\/elife.108959","type":"journal-article","created":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T14:30:45Z","timestamp":1764599445000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.108959","source":"Crossref","is-referenced-by-count":1,"title":["Bivalent mRNA booster encoding virus-like particles elicits potent polyclass receptor-binding domain antibodies in pre-vaccinated mice"],"prefix":"10.7554","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4213-5758","authenticated-orcid":true,"given":"Chengcheng","family":"Fan","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05dxps055","id-type":"ROR","asserted-by":"publisher"}],"name":"Division of Biology and Biological Engineering, California Institute of Technology","place":["Pasadena, United States"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"conceptualization","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2818-656X","authenticated-orcid":true,"given":"Alexander A","family":"Cohen","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05dxps055","id-type":"ROR","asserted-by":"publisher"}],"name":"Division of Biology and Biological Engineering, California Institute of Technology","place":["Pasadena, United States"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"conceptualization","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1416-4757","authenticated-orcid":true,"given":"Kim-Marie A","family":"Dam","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/038321296","id-type":"ROR","asserted-by":"publisher"}],"name":"Gladstone Institutes","place":["San Francisco, United States"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"conceptualization","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Annie V","family":"Rorick","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05dxps055","id-type":"ROR","asserted-by":"publisher"}],"name":"Division of Biology and Biological Engineering, California Institute of Technology","place":["Pasadena, United States"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"data-curation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"}]},{"given":"Ange-C\u00e9lia I","family":"Priso Fils","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05dxps055","id-type":"ROR","asserted-by":"publisher"}],"name":"Division of Biology and Biological Engineering, California Institute of Technology","place":["Pasadena, United States"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"data-curation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8680-3784","authenticated-orcid":true,"given":"Zhi","family":"Yang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05dxps055","id-type":"ROR","asserted-by":"publisher"}],"name":"Division of Biology and Biological Engineering, California Institute of Technology","place":["Pasadena, United States"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"data-curation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"}]},{"given":"Priyanthi NP","family":"Gnanapragasam","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05dxps055","id-type":"ROR","asserted-by":"publisher"}],"name":"Division of Biology and Biological Engineering, California Institute of Technology","place":["Pasadena, United States"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"data-curation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"}]},{"given":"Luisa N","family":"Segovia","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05dxps055","id-type":"ROR","asserted-by":"publisher"}],"name":"Division of Biology and Biological Engineering, California Institute of Technology","place":["Pasadena, United States"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"data-curation","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"}]},{"given":"Kathryn E","family":"Huey-Tubman","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05dxps055","id-type":"ROR","asserted-by":"publisher"}],"name":"Division of Biology and Biological Engineering, California Institute of Technology","place":["Pasadena, United States"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"data-curation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"}]},{"given":"Woohyun J","family":"Moon","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04eaec870","id-type":"ROR","asserted-by":"publisher"}],"name":"Acuitas Therapeutics","place":["Vancouver, Canada"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"methodology","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"}]},{"given":"Paulo JC","family":"Lin","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04eaec870","id-type":"ROR","asserted-by":"publisher"}],"name":"Acuitas Therapeutics","place":["Vancouver, Canada"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"methodology","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2277-3990","authenticated-orcid":true,"given":"Pamela J","family":"Bjorkman","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05dxps055","id-type":"ROR","asserted-by":"publisher"}],"name":"Division of Biology and Biological Engineering, California Institute of Technology","place":["Pasadena, United States"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"corresponding-author","vocabulary":"crossref"},{"role":"conceptualization","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4923-9568","authenticated-orcid":true,"given":"Magnus AG","family":"Hoffmann","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/038321296","id-type":"ROR","asserted-by":"publisher"}],"name":"Gladstone Institutes","place":["San Francisco, United States"]},{"id":[{"id":"https:\/\/ror.org\/043mz5j54","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Medicine, University of California, San Francisco","place":["San Francisco, United States"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"corresponding-author","vocabulary":"crossref"},{"role":"conceptualization","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]}],"member":"4374","published-online":{"date-parts":[[2026,4,30]]},"reference":[{"key":"bib1","doi-asserted-by":"publisher","first-page":"592","DOI":"10.1038\/s41586-023-06025-4","type":"journal-article","article-title":"SARS-CoV-2 Omicron boosting induces de novo B cell response in humans","volume":"617","author":"Alsoussi","year":"2023","journal-title":"Nature"},{"key":"bib2","doi-asserted-by":"publisher","first-page":"1532","DOI":"10.1056\/NEJMoa2119451","type":"journal-article","article-title":"Covid-19 vaccine effectiveness against the Omicron (B.1.1.529) variant","volume":"386","author":"Andrews","year":"2022","journal-title":"The New England Journal of Medicine"},{"key":"bib3","doi-asserted-by":"publisher","first-page":"831","DOI":"10.1038\/s41591-022-01699-1","type":"journal-article","article-title":"Effectiveness of COVID-19 booster vaccines against COVID-19-related symptoms, hospitalization and death in England","volume":"28","author":"Andrews","year":"2022","journal-title":"Nature Medicine"},{"key":"bib4","doi-asserted-by":"publisher","first-page":"403","DOI":"10.1056\/NEJMoa2035389","type":"journal-article","article-title":"Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine","volume":"384","author":"Baden","year":"2021","journal-title":"New England Journal of Medicine"},{"key":"bib5","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1266829","type":"journal-article","article-title":"Antibodies to S2 domain of SARS-CoV-2 spike protein in Moderna mRNA vaccinated subjects sustain antibody-dependent NK cell-mediated cell cytotoxicity against Omicron BA.1","volume":"14","author":"Balinsky","year":"2023","journal-title":"Frontiers in Immunology"},{"key":"bib6","doi-asserted-by":"publisher","first-page":"682","DOI":"10.1038\/s41586-020-2852-1","type":"journal-article","article-title":"SARS-CoV-2 neutralizing antibody structures inform therapeutic strategies","volume":"588","author":"Barnes","year":"2020","journal-title":"Nature"},{"key":"bib7","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.adf1421","type":"journal-article","article-title":"SARS-CoV-2 spike conformation determines plasma neutralizing activity elicited by a wide panel of human vaccines","volume":"7","author":"Bowen","year":"2022","journal-title":"Science Immunology"},{"key":"bib8","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2023.112014","type":"journal-article","article-title":"Bivalent intra-spike binding provides durability against emergent Omicron lineages: Results from a global consortium","volume":"42","author":"Callaway","year":"2023","journal-title":"Cell Reports"},{"key":"bib9","doi-asserted-by":"publisher","DOI":"10.1016\/S2666-5247(23)00118-0","type":"journal-article","article-title":"Bivalent COVID-19 booster vaccines and the absence of BA.5-specific antibodies","volume":"4","author":"Carre\u00f1o","year":"2023","journal-title":"The Lancet. Microbe"},{"key":"bib10","doi-asserted-by":"publisher","first-page":"654","DOI":"10.1038\/s41586-021-04387-1","type":"journal-article","article-title":"Omicron extensively but incompletely escapes Pfizer BNT162b2 neutralization","volume":"602","author":"Cele","year":"2022","journal-title":"Nature"},{"key":"bib11","doi-asserted-by":"publisher","first-page":"1279","DOI":"10.1056\/NEJMoa2208343","type":"journal-article","article-title":"A bivalent Omicron-containing booster vaccine against Covid-19","volume":"387","author":"Chalkias","year":"2022","journal-title":"The New England Journal of Medicine"},{"key":"bib12","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1038\/s41577-022-00784-3","type":"journal-article","article-title":"Broadly neutralizing antibodies to SARS-CoV-2 and other human coronaviruses","volume":"23","author":"Chen","year":"2023","journal-title":"Nature Reviews. Immunology"},{"key":"bib13","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1016\/j.coviro.2016.12.004","type":"journal-article","article-title":"Immune history and influenza virus susceptibility","volume":"22","author":"Cobey","year":"2017","journal-title":"Current Opinion in Virology"},{"key":"bib14","doi-asserted-by":"publisher","first-page":"735","DOI":"10.1126\/science.abf6840","type":"journal-article","article-title":"Mosaic nanoparticles elicit cross-reactive immune responses to zoonotic coronaviruses in mice","volume":"371","author":"Cohen","year":"2021","journal-title":"Science"},{"key":"bib15","doi-asserted-by":"publisher","DOI":"10.1126\/science.abq0839","type":"journal-article","article-title":"Mosaic RBD nanoparticles protect against challenge by diverse sarbecoviruses in animal models","volume":"377","author":"Cohen","year":"2022","journal-title":"Science"},{"key":"bib16","doi-asserted-by":"publisher","first-page":"5554","DOI":"10.1016\/j.cell.2024.07.052","type":"journal-article","article-title":"Mosaic sarbecovirus nanoparticles elicit cross-reactive responses in pre-vaccinated animals","volume":"187","author":"Cohen","year":"2024","journal-title":"Cell"},{"key":"bib17","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1056\/NEJMc2213948","type":"journal-article","article-title":"Immunogenicity of BA.5 bivalent mRNA vaccine boosters","volume":"388","author":"Collier","year":"2023","journal-title":"The New England Journal of Medicine"},{"key":"bib18","doi-asserted-by":"publisher","first-page":"567","DOI":"10.1038\/s41586-020-2622-0","type":"journal-article","article-title":"SARS-CoV-2 mRNA vaccine design enabled by prototype pathogen preparedness","volume":"586","author":"Corbett","year":"2020","journal-title":"Nature"},{"key":"bib19","doi-asserted-by":"publisher","DOI":"10.3390\/v12050513","type":"journal-article","article-title":"Protocol and reagents for Pseudotyping lentiviral particles with SARS-CoV-2 spike protein for neutralization assays","volume":"12","author":"Crawford","year":"2020","journal-title":"Viruses"},{"key":"bib20","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1056\/NEJMc2214293","type":"journal-article","article-title":"Neutralization against BA.2.75.2, BQ.1.1, and XBB from mRNA bivalent booster","volume":"388","author":"Davis-Gardner","year":"2023","journal-title":"The New England Journal of Medicine"},{"key":"bib21","doi-asserted-by":"publisher","first-page":"2419","DOI":"10.1016\/j.immuni.2022.10.019","type":"journal-article","article-title":"Neutralizing monoclonal antibodies elicited by mosaic RBD nanoparticles bind conserved sarbecovirus epitopes","volume":"55","author":"Fan","year":"2022","journal-title":"Immunity"},{"key":"bib22","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2501637122","type":"journal-article","article-title":"Cross-reactive sarbecovirus antibodies induced by mosaic RBD nanoparticles","volume":"122","author":"Fan","year":"2025","journal-title":"PNAS"},{"key":"bib23","doi-asserted-by":"publisher","first-page":"2032","DOI":"10.1038\/s41591-021-01540-1","type":"journal-article","article-title":"Correlates of protection against symptomatic and asymptomatic SARS-CoV-2 infection","volume":"27","author":"Feng","year":"2021","journal-title":"Nature Medicine"},{"key":"bib24","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1016\/j.chom.2021.02.003","type":"journal-article","article-title":"Comprehensive mapping of mutations in the SARS-CoV-2 receptor-binding domain that affect recognition by polyclonal human plasma antibodies","volume":"29","author":"Greaney","year":"2021","journal-title":"Cell Host & Microbe"},{"key":"bib25","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-24435-8","type":"journal-article","article-title":"Mapping mutations to the SARS-CoV-2 RBD that escape binding by different classes of antibodies","volume":"12","author":"Greaney","year":"2021","journal-title":"Nature Communications"},{"key":"bib26","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1038\/s41591-021-01676-0","type":"journal-article","article-title":"mRNA booster immunization elicits potent neutralizing serum activity against the SARS-CoV-2 Omicron variant","volume":"28","author":"Gruell","year":"2022","journal-title":"Nature Medicine"},{"key":"bib27","doi-asserted-by":"publisher","first-page":"1216","DOI":"10.1038\/s41565-024-01655-9","type":"journal-article","article-title":"Proactive vaccination using multiviral Quartet Nanocages to elicit broad anti-coronavirus responses","volume":"19","author":"Hills","year":"2024","journal-title":"Nature Nanotechnology"},{"key":"bib28","doi-asserted-by":"publisher","first-page":"2380","DOI":"10.1016\/j.cell.2023.04.024","type":"journal-article","article-title":"ESCRT recruitment to SARS-CoV-2 spike induces virus-like particles that improve mRNA vaccines","volume":"186","author":"Hoffmann","year":"2023","journal-title":"Cell"},{"key":"bib29","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1146\/annurev-med-042420-112725","type":"journal-article","article-title":"mRNA Vaccines in the COVID-19 Pandemic and Beyond","volume":"73","author":"Hogan","year":"2022","journal-title":"Annual Review of Medicine"},{"key":"bib30","doi-asserted-by":"publisher","first-page":"1501","DOI":"10.1126\/science.abd0826","type":"journal-article","article-title":"Structure-based design of prefusion-stabilized SARS-CoV-2 spikes","volume":"369","author":"Hsieh","year":"2020","journal-title":"Science"},{"key":"bib31","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-45404-x","type":"journal-article","article-title":"Prefusion-stabilized SARS-CoV-2 S2-only antigen provides protection against SARS-CoV-2 challenge","volume":"15","author":"Hsieh","year":"2024","journal-title":"Nature Communications"},{"key":"bib32","doi-asserted-by":"publisher","first-page":"1833","DOI":"10.1038\/mt.2008.200","type":"journal-article","article-title":"Incorporation of pseudouridine into mRNA yields superior nonimmunogenic vector with increased translational capacity and biological stability","volume":"16","author":"Karik\u00f3","year":"2008","journal-title":"Molecular Therapy"},{"key":"bib33","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkr695","type":"journal-article","article-title":"Generating the optimal mRNA for therapy: HPLC purification eliminates immune activation and improves translation of nucleoside-modified, protein-encoding mRNA","volume":"39","author":"Karik\u00f3","year":"2011","journal-title":"Nucleic Acids Research"},{"key":"bib34","doi-asserted-by":"publisher","first-page":"488","DOI":"10.1038\/s41586-022-04460-3","type":"journal-article","article-title":"T cell responses to SARS-CoV-2 spike cross-recognize Omicron","volume":"603","author":"Keeton","year":"2022","journal-title":"Nature"},{"key":"bib35","doi-asserted-by":"publisher","first-page":"574","DOI":"10.1038\/s41591-023-02228-4","type":"journal-article","article-title":"Predicting the efficacy of variant-modified COVID-19 vaccine boosters","volume":"29","author":"Khoury","year":"2023","journal-title":"Nature Medicine"},{"key":"bib36","doi-asserted-by":"publisher","first-page":"812","DOI":"10.1016\/j.cell.2020.06.043","type":"journal-article","article-title":"Tracking changes in SARS-CoV-2 Spike: Evidence that D614G increases infectivity of the COVID-19 virus","volume":"182","author":"Korber","year":"2020","journal-title":"Cell"},{"key":"bib37","doi-asserted-by":"publisher","first-page":"W299","DOI":"10.1093\/nar\/gki370","type":"journal-article","article-title":"ConSurf 2005: The projection of evolutionary conservation scores of residues on protein structures","volume":"33","author":"Landau","year":"2005","journal-title":"Nucleic Acids Research"},{"key":"bib38","doi-asserted-by":"publisher","DOI":"10.1080\/22221751.2023.2220582","type":"journal-article","article-title":"SARS-CoV-2 spike S2-specific neutralizing antibodies","volume":"12","author":"Li","year":"2023","journal-title":"Emerging Microbes & Infections"},{"key":"bib39","doi-asserted-by":"publisher","first-page":"676","DOI":"10.1038\/s41586-021-04388-0","type":"journal-article","article-title":"Striking antibody evasion manifested by the Omicron variant of SARS-CoV-2","volume":"602","author":"Liu","year":"2022","journal-title":"Nature"},{"key":"bib40","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1016\/j.jsb.2005.07.007","type":"journal-article","article-title":"Automated electron microscope tomography using robust prediction of specimen movements","volume":"152","author":"Mastronarde","year":"2005","journal-title":"Journal of Structural Biology"},{"key":"bib41","doi-asserted-by":"publisher","first-page":"2418","DOI":"10.1128\/JVI.02146-06","type":"journal-article","article-title":"The Cytoplasmic tail of the severe acute respiratory syndrome coronavirus spike protein contains a novel endoplasmic reticulum retrieval signal that binds COPI and promotes interaction with membrane protein","volume":"81","author":"McBride","year":"2007","journal-title":"Journal of Virology"},{"key":"bib42","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1016\/0092-8674(89)90846-5","type":"journal-article","article-title":"Fc receptor isoforms exhibit distinct abilities for coated pit localization as a result of cytoplasmic domain heterogeneity","volume":"58","author":"Miettinen","year":"1989","journal-title":"Cell"},{"key":"bib43","doi-asserted-by":"publisher","first-page":"662","DOI":"10.1056\/NEJMc2214314","type":"journal-article","article-title":"Substantial neutralization escape by SARS-CoV-2 Omicron variants BQ.1.1 and XBB.1","volume":"388","author":"Miller","year":"2023","journal-title":"New England Journal of Medicine"},{"key":"bib44","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.ade9888","type":"journal-article","article-title":"Exposure to BA.4\/5 S protein drives neutralization of Omicron BA.1, BA.2, BA.2.12.1, and BA.4\/5 in vaccine-experienced humans and mice","volume":"7","author":"Muik","year":"2022","journal-title":"Science Immunology"},{"key":"bib45","doi-asserted-by":"publisher","first-page":"268","DOI":"10.1038\/s41586-021-03841-4","type":"journal-article","article-title":"Rapid and stable mobilization of CD8+ T cells by SARS-CoV-2 mRNA vaccine","volume":"597","author":"Oberhardt","year":"2021","journal-title":"Nature"},{"key":"bib46","doi-asserted-by":"publisher","first-page":"2133","DOI":"10.1016\/j.immuni.2021.08.001","type":"journal-article","article-title":"Rapid induction of antigen-specific CD4+ T cells is associated with coordinated humoral and cellular immunity to SARS-CoV-2 mRNA vaccination","volume":"54","author":"Painter","year":"2021","journal-title":"Immunity"},{"key":"bib47","doi-asserted-by":"publisher","first-page":"E7348","DOI":"10.1073\/pnas.1707304114","type":"journal-article","article-title":"Immunogenicity and structures of a rationally designed prefusion MERS-CoV spike antigen","volume":"114","author":"Pallesen","year":"2017","journal-title":"PNAS"},{"key":"bib48","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1016\/j.jconrel.2015.08.007","type":"journal-article","article-title":"Expression kinetics of nucleoside-modified mRNA delivered in lipid nanoparticles to mice by various routes","volume":"217","author":"Pardi","year":"2015","journal-title":"Journal of Controlled Release"},{"key":"bib49","doi-asserted-by":"publisher","first-page":"619","DOI":"10.1126\/science.adc9127","type":"journal-article","article-title":"Imprinted antibody responses against SARS-CoV-2 Omicron sublineages","volume":"378","author":"Park","year":"2022","journal-title":"Science"},{"key":"bib50","doi-asserted-by":"publisher","first-page":"1109","DOI":"10.1126\/science.abj3321","type":"journal-article","article-title":"Broad betacoronavirus neutralization by a stem helix-specific human antibody","volume":"373","author":"Pinto","year":"2021","journal-title":"Science"},{"key":"bib51","doi-asserted-by":"publisher","first-page":"276","DOI":"10.1038\/s41586-021-03777-9","type":"journal-article","article-title":"Reduced sensitivity of SARS-CoV-2 variant Delta to antibody neutralization","volume":"596","author":"Planas","year":"2021","journal-title":"Nature"},{"key":"bib52","doi-asserted-by":"publisher","first-page":"2603","DOI":"10.1056\/NEJMoa2034577","type":"journal-article","article-title":"Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine","volume":"383","author":"Polack","year":"2020","journal-title":"The New England Journal of Medicine"},{"key":"bib53","doi-asserted-by":"publisher","first-page":"290","DOI":"10.1038\/nmeth.4169","type":"journal-article","article-title":"cryoSPARC: Algorithms for rapid unsupervised cryo-EM structure determination","volume":"14","author":"Punjani","year":"2017","journal-title":"Nature Methods"},{"key":"bib54","doi-asserted-by":"publisher","first-page":"437","DOI":"10.1038\/s41586-020-2456-9","type":"journal-article","article-title":"Convergent antibody responses to SARS-CoV-2 in convalescent individuals","volume":"584","author":"Robbiani","year":"2020","journal-title":"Nature"},{"key":"bib55","doi-asserted-by":"publisher","first-page":"996","DOI":"10.1016\/j.cell.2020.09.038","type":"journal-article","article-title":"Antigen-specific adaptive immunity to SARS-CoV-2 in acute COVID-19 and associations with age and disease severity","volume":"183","author":"Rydyznski Moderbacher","year":"2020","journal-title":"Cell"},{"key":"bib56","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1003618","type":"journal-article","article-title":"A next-generation cleaved, soluble HIV-1 Env Trimer, BG505 SOSIP.664 gp140, expresses multiple epitopes for broadly neutralizing but not non-neutralizing antibodies","volume":"9","author":"Sanders","year":"2013","journal-title":"PLOS Pathogens"},{"key":"bib57","doi-asserted-by":"publisher","first-page":"1155","DOI":"10.1126\/science.1061692","type":"journal-article","article-title":"Crystal structure of a neutralizing human IGG against HIV-1: A template for vaccine design","volume":"293","author":"Saphire","year":"2001","journal-title":"Science"},{"key":"bib58","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1038\/s41591-022-02092-8","type":"journal-article","article-title":"Bivalent SARS-CoV-2 mRNA vaccines increase breadth of neutralization and protect against the BA.5 Omicron variant in mice","volume":"29","author":"Scheaffer","year":"2023","journal-title":"Nature Medicine"},{"key":"bib59","doi-asserted-by":"publisher","first-page":"3389","DOI":"10.1016\/j.vaccine.2024.04.049","type":"journal-article","article-title":"A systematic review and meta-analysis on the effectiveness of bivalent mRNA booster vaccines against Omicron variants","volume":"42","author":"Song","year":"2024","journal-title":"Vaccine"},{"key":"bib60","doi-asserted-by":"publisher","first-page":"1295","DOI":"10.1016\/j.cell.2020.08.012","type":"journal-article","article-title":"Deep mutational scanning of SARS-CoV-2 receptor binding domain reveals constraints on folding and ACE2 binding","volume":"182","author":"Starr","year":"2020","journal-title":"Cell"},{"key":"bib61","doi-asserted-by":"publisher","first-page":"420","DOI":"10.1126\/science.abo7896","type":"journal-article","article-title":"Shifting mutational constraints in the SARS-CoV-2 receptor-binding domain during viral evolution","volume":"377","author":"Starr","year":"2022","journal-title":"Science"},{"key":"bib62","doi-asserted-by":"publisher","first-page":"1343","DOI":"10.1016\/S1473-3099(23)00373-0","type":"journal-article","article-title":"Effectiveness of bivalent mRNA vaccines against medically attended symptomatic SARS-CoV-2 infection and COVID-19-related hospital admission among SARS-CoV-2-naive and previously infected individuals: a retrospective cohort study","volume":"23","author":"Tan","year":"2023","journal-title":"The Lancet Infectious Diseases"},{"key":"bib63","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1011901","type":"journal-article","article-title":"Deep mutational scans of XBB.1.5 and BQ.1.1 reveal ongoing epistatic drift during SARS-CoV-2 evolution","volume":"19","author":"Taylor","year":"2023","journal-title":"PLOS Pathogens"},{"key":"bib64","doi-asserted-by":"publisher","first-page":"1063","DOI":"10.1038\/s41591-022-01753-y","type":"journal-article","article-title":"Effectiveness of mRNA-1273 against SARS-CoV-2 Omicron and delta variants","volume":"28","author":"Tseng","year":"2022","journal-title":"Nature Medicine"},{"key":"bib65","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1016\/j.cell.2020.02.058","type":"journal-article","article-title":"Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein","volume":"181","author":"Walls","year":"2020","journal-title":"Cell"},{"key":"bib66","doi-asserted-by":"publisher","first-page":"998","DOI":"10.1016\/j.immuni.2022.04.003","type":"journal-article","article-title":"Analysis of memory B cells identifies conserved neutralizing epitopes on the N-terminal domain of variant SARS-Cov-2 spike proteins","volume":"55","author":"Wang","year":"2022","journal-title":"Immunity"},{"key":"bib67","doi-asserted-by":"publisher","first-page":"527","DOI":"10.1016\/S1473-3099(23)00181-0","type":"journal-article","article-title":"SARS-CoV-2 neutralising antibodies after bivalent versus monovalent booster","volume":"23","author":"Wang","year":"2023","journal-title":"The Lancet. Infectious Diseases"},{"key":"bib68","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2023.101258","type":"journal-article","article-title":"Deep immunological imprinting due to the ancestral spike in the current bivalent COVID-19 vaccine","volume":"4","author":"Wang","year":"2023","journal-title":"Cell Reports Medicine"},{"key":"bib69","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1016\/j.cell.2022.12.018","type":"journal-article","article-title":"Alarming antibody evasion properties of rising SARS-CoV-2 BQ and XBB subvariants","volume":"186","author":"Wang","year":"2023","journal-title":"Cell"},{"key":"bib70","doi-asserted-by":"publisher","first-page":"10598","DOI":"10.1073\/pnas.1309215110","type":"journal-article","article-title":"Computational analysis of anti\u2013HIV-1 antibody neutralization panel data to identify potential functional epitope residues","volume":"110","author":"West","year":"2013","journal-title":"PNAS"},{"key":"bib71","type":"web-resource","article-title":"Classification of Omicron (B.1.1.529): SARS\u2010CoV\u20102 variant of concern","author":"WHO","year":"2021","unstructured":"WHO. 2021. Classification of Omicron (B.1.1.529): SARS\u2010CoV\u20102 variant of concern. https:\/\/www.who.int\/news\/item\/26-11-2021-classification-of-omicron-(b.1.1.529)-sars-cov-2-variant-of-concern [Accessed November 26, 2021]."},{"key":"bib72","doi-asserted-by":"publisher","first-page":"1260","DOI":"10.1126\/science.abb2507","type":"journal-article","article-title":"Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation","volume":"367","author":"Wrapp","year":"2020","journal-title":"Science"},{"key":"bib73","doi-asserted-by":"publisher","first-page":"1572","DOI":"10.1016\/j.cell.2022.03.037","type":"journal-article","article-title":"Boosting with variant-matched or historical mRNA vaccines protects against Omicron infection in mice","volume":"185","author":"Ying","year":"2022","journal-title":"Cell"},{"key":"bib74","doi-asserted-by":"publisher","first-page":"2434","DOI":"10.1016\/j.cell.2022.05.022","type":"journal-article","article-title":"Humoral and cellular immune memory to four COVID-19 vaccines","volume":"185","author":"Zhang","year":"2022","journal-title":"Cell"},{"key":"bib75","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1016\/j.ijid.2021.11.009","type":"journal-article","article-title":"Real-world effectiveness of COVID-19 vaccines: a literature review and meta-analysis","volume":"114","author":"Zheng","year":"2022","journal-title":"International Journal of Infectious Diseases"},{"key":"dataset1","type":"dataset","article-title":"SARS-CoV-2 RBD mutational antig Illumina barcode sequencing for XBB15_22_gp8_81_250_abneg","volume-title":"NCBI Sequence Read Archive","author":"California Institute of Technology","year":"2026","unstructured":"California Institute of Technology. 2026. SARS-CoV-2 RBD mutational antig Illumina barcode sequencing for XBB15_22_gp8_81_250_abneg. NCBI Sequence Read Archive. https:\/\/www.ncbi.nlm.nih.gov\/sra\/SRX32770151. SRX32770151."},{"key":"dataset2","type":"dataset","article-title":"SARS-CoV-2 Wuhan-Hu-1\/BA.1 spike heterotrimer (HT2) with 3-'down' RBDs","volume-title":"EMDataBank","author":"Fan","year":"2025","unstructured":"Fan C, Dam KA, Bjorkman PJ. 2025. SARS-CoV-2 Wuhan-Hu-1\/BA.1 spike heterotrimer (HT2) with 3-'down' RBDs. EMDataBank. https:\/\/emdataresource.org\/EMD-71513. EMD-71513."},{"key":"dataset3","type":"dataset","article-title":"SARS-CoV-2 Wuhan-Hu-1\/BA.1 spike heterotrimer (HT2) with 1-'up' RBD","volume-title":"EMDataBank","author":"Fan","year":"2025","unstructured":"Fan C, Dam KA, Bjorkman PJ. 2025. SARS-CoV-2 Wuhan-Hu-1\/BA.1 spike heterotrimer (HT2) with 1-'up' RBD. EMDataBank. https:\/\/emdataresource.org\/EMD-71514. EMD-71514."},{"key":"dataset4","type":"dataset","article-title":"SARS-CoV-2 Wuhan-Hu-1\/BA.1\/Delta spike heterotrimer (HT3) with 3-'down' RBDs","volume-title":"EMDataBank","author":"Fan","year":"2025","unstructured":"Fan C, Dam KA, Bjorkman PJ. 2025. SARS-CoV-2 Wuhan-Hu-1\/BA.1\/Delta spike heterotrimer (HT3) with 3-'down' RBDs. EMDataBank. https:\/\/emdataresource.org\/EMD-71515. EMD-71515."},{"key":"dataset5","type":"dataset","article-title":"SARS-CoV-2 Wuhan-Hu-1\/BA.1\/Delta spike heterotrimer (HT3) with 1-'up' RBD","volume-title":"EMDataBank","author":"Fan","year":"2025","unstructured":"Fan C, Dam KA, Bjorkman PJ. 2025. SARS-CoV-2 Wuhan-Hu-1\/BA.1\/Delta spike heterotrimer (HT3) with 1-'up' RBD. EMDataBank. https:\/\/emdataresource.org\/EMD-71516. EMD-71516."}],"container-title":["eLife"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/cdn.elifesciences.org\/articles\/108959\/elife-108959-v1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/cdn.elifesciences.org\/articles\/108959\/elife-108959-v1.xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/elifesciences.org\/articles\/108959","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T09:02:28Z","timestamp":1787562148000},"score":1,"resource":{"primary":{"URL":"https:\/\/elifesciences.org\/articles\/108959"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,30]]},"references-count":80,"alternative-id":["10.7554\/eLife.108959"],"URL":"https:\/\/doi.org\/10.7554\/elife.108959","archive":["CLOCKSS"],"relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2025.08.18.670983","asserted-by":"subject"},{"id-type":"doi","id":"10.1101\/2025.08.18.670983","asserted-by":"object"}],"is-same-as":[{"id-type":"doi","id":"10.7554\/eLife.108959.3","asserted-by":"subject"}],"is-version-of":[{"id-type":"doi","id":"10.7554\/eLife.108959.1","asserted-by":"subject"},{"id-type":"doi","id":"10.7554\/eLife.108959.2","asserted-by":"subject"}],"is-supplemented-by":[{"id-type":"accession","id":"SRX32770151","asserted-by":"subject"},{"id-type":"accession","id":"EMD-71513","asserted-by":"subject"},{"id-type":"accession","id":"EMD-71514","asserted-by":"subject"},{"id-type":"accession","id":"EMD-71515","asserted-by":"subject"},{"id-type":"accession","id":"EMD-71516","asserted-by":"subject"}]},"ISSN":["2050-084X"],"issn-type":[{"value":"2050-084X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,30]]},"assertion":[{"value":"single anonymised","name":"peer_review_transparency","label":"Peer review transparency","group":{"name":"peer_review_taxonomy"}},{"value":"other reviewer(s), editor","name":"peer_review_interaction","label":"Peer review interaction","group":{"name":"peer_review_taxonomy"}},{"value":"review summaries, review reports, author\/editor communication, reviewer identities reviewer opt in, editor identities","name":"peer_review_published","label":"Peer review published","group":{"name":"peer_review_taxonomy"}},{"value":"open (sign in with ORCID iD required)","name":"post_publication_commenting","label":"Post publication commenting","group":{"name":"post_publication_commenting"}}],"article-number":"RP108959"}}