eLifeApr 30, 2026

Bivalent mRNA booster triggers strong mixed antibody response targeting the virus in previously vaccinated mice

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗

Updated May 1, 2026

Abstract

Bivalent S-EABR mRNA-LNP boosters consistently elicited the highest neutralizing antibody titers against Omicron subvariants in mice with pre-existing immunity.

Monovalent and bivalent S-EABR mRNA-LNP boosters enhanced neutralizing responses compared to conventional boosters.
Bivalent S-EABR mRNA-LNP boosted diverse anti-receptor-binding domain responses, indicating balanced targeting of multiple epitope classes.
Conventional boosters elicited less diverse serum responses, primarily focusing on dominant RBD epitopes.
Cryo-electron microscopy revealed that bivalent immunizations promote S heterotrimer formation, which may enhance antibody breadth.
These findings suggest that bivalent or multivalent S-EABR mRNA-LNP boosters could provide broader protection against SARS-CoV-2 variants.

Simplified

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.

Funding

Competing interests

CF, AC, KD, AR, AP, ZY, PG, LS, KH No competing interests declared, WM employee of Acuitas Therapeutics, a company developing lipid nanoparticle delivery technology, PL employee of Acuitas Therapeutics, a company developing lipid nanoparticle delivery technology; holds equity in Acuitas Therapeutics, PB inventor on a US patent application filed by the California Institute of Technology that covers the EABR technology described in this work; is a scientific advisor for Vaccine Company, Inc, MH inventor on a US patent application filed by the California Institute of Technology that covers the EABR technology described in this work; is a scientific consultant for Vaccine Company, Inc

PubMed

Bivalent mRNA booster triggers strong mixed antibody response targeting the virus in previously vaccinated mice

Abstract

Funding

Competing interests

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