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Bivalent mRNA booster encoding virus-like particles elicits potent polyclass RBD antibodies in pre-vaccinated mice.

作者信息

Fan Chengcheng, Cohen Alexander A, Dam Kim-Marie A, Rorick Annie V, Priso Fils Ange-Célia I, Yang Zhi, Gnanapragasam Priyanthi N P, Segovia Luisa N, Huey-Tubman Kathryn E, Moon Woohyun J, Lin Paulo J C, Bjorkman Pamela J, Hoffmann Magnus A G

机构信息

Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.

These authors contributed equally.

出版信息

bioRxiv. 2025 Aug 19:2025.08.18.670983. doi: 10.1101/2025.08.18.670983.


DOI:10.1101/2025.08.18.670983
PMID:40894670
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12393457/
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-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-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.

摘要
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79bb/12393457/3726275354d6/nihpp-2025.08.18.670983v1-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79bb/12393457/ed6029db6279/nihpp-2025.08.18.670983v1-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79bb/12393457/d2b212bf8390/nihpp-2025.08.18.670983v1-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79bb/12393457/acff0a7b12fa/nihpp-2025.08.18.670983v1-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79bb/12393457/dac2fb203353/nihpp-2025.08.18.670983v1-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79bb/12393457/3726275354d6/nihpp-2025.08.18.670983v1-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79bb/12393457/ed6029db6279/nihpp-2025.08.18.670983v1-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79bb/12393457/d2b212bf8390/nihpp-2025.08.18.670983v1-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79bb/12393457/acff0a7b12fa/nihpp-2025.08.18.670983v1-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79bb/12393457/dac2fb203353/nihpp-2025.08.18.670983v1-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79bb/12393457/3726275354d6/nihpp-2025.08.18.670983v1-f0005.jpg

相似文献

[1]
Bivalent mRNA booster encoding virus-like particles elicits potent polyclass RBD antibodies in pre-vaccinated mice.

bioRxiv. 2025-8-19

[2]
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[3]
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[4]
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[5]
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[6]
Fourth dose bivalent COVID-19 vaccines outperform monovalent boosters in eliciting cross-reactive memory B cells to Omicron subvariants.

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[7]
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[8]
ESCRT recruitment to mRNA-encoded SARS-CoV-2 spike induces virus-like particles and enhanced antibody responses.

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[9]
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J Virol. 2025-7-22

[10]
Safety and immunogenicity of booster doses of an XBB.1.5 RBD subunit COVID-19 vaccine among individuals aged 5-80 years in India: a phase 3, single-blind, randomised controlled trial.

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本文引用的文献

[1]
Cross-reactive sarbecovirus antibodies induced by mosaic RBD nanoparticles.

Proc Natl Acad Sci U S A. 2025-5-27

[2]
Mosaic sarbecovirus nanoparticles elicit cross-reactive responses in pre-vaccinated animals.

Cell. 2024-10-3

[3]
Proactive vaccination using multiviral Quartet Nanocages to elicit broad anti-coronavirus responses.

Nat Nanotechnol. 2024-8

[4]
A systematic review and meta-analysis on the effectiveness of bivalent mRNA booster vaccines against Omicron variants.

Vaccine. 2024-5-31

[5]
Prefusion-stabilized SARS-CoV-2 S2-only antigen provides protection against SARS-CoV-2 challenge.

Nat Commun. 2024-2-20

[6]
Deep mutational scans of XBB.1.5 and BQ.1.1 reveal ongoing epistatic drift during SARS-CoV-2 evolution.

PLoS Pathog. 2023-12

[7]
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.

Front Immunol. 2023

[8]
Deep immunological imprinting due to the ancestral spike in the current bivalent COVID-19 vaccine.

Cell Rep Med. 2023-11-21

[9]
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.

Lancet Infect Dis. 2023-12

[10]
SARS-CoV-2 spike S2-specific neutralizing antibodies.

Emerg Microbes Infect. 2023-12

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