{"doi":"10.7554/elife.108959","title":"Bivalent mRNA booster encoding virus-like particles elicits potent polyclass receptor-binding domain antibodies in pre-vaccinated mice","abstract":"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 naïve 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 'polyclass' 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.","journal":"eLife","year":2025,"id":583739,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9508,"is_data_producer":true,"deposit_databanks":{"SRA":["SRX32770151"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":16982,"name":"Alexander A. Cohen","orcid":"0000-0002-2818-656X","position":1,"is_corresponding":false},{"id":105096,"name":"Kim-Marie A. Dam","orcid":"0000-0002-1416-4757","position":2,"is_corresponding":false},{"id":1204088,"name":"Annie V. Rorick","orcid":"0009-0003-1801-6940","position":3,"is_corresponding":false},{"id":1460033,"name":"Ange-Célia I Priso Fils","orcid":null,"position":4,"is_corresponding":false},{"id":614448,"name":"Zhi Yang","orcid":"0000-0001-8680-3784","position":5,"is_corresponding":false},{"id":16983,"name":"Priyanthi N.P. Gnanapragasam","orcid":null,"position":6,"is_corresponding":false},{"id":1496710,"name":"Luisa N Segovia","orcid":null,"position":7,"is_corresponding":false},{"id":16998,"name":"Kathryn E. Huey‐Tubman","orcid":"0000-0002-4683-8138","position":8,"is_corresponding":false},{"id":1366024,"name":"Woohyun J Moon","orcid":null,"position":9,"is_corresponding":false},{"id":234005,"name":"Paulo J.C. Lin","orcid":null,"position":10,"is_corresponding":false},{"id":17000,"name":"Pamela J. Björkman","orcid":"0000-0002-2277-3990","position":11,"is_corresponding":false},{"id":107613,"name":"Magnus A. G. Hoffmann","orcid":"0000-0003-4923-9568","position":12,"is_corresponding":false},{"id":455047,"name":"Chengcheng Fan","orcid":"0000-0003-4213-5758","position":0,"is_corresponding":true}],"reference_count":72,"raw_metadata":null,"created_at":"2026-07-19T02:59:07.970345Z","pmid":"42059889","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}