Movie
Controller
Structure viewers
About Yorodumi Papers
+Search query
-Structure paper
| Title | Bivalent mRNA booster encoding virus-like particles elicits potent polyclass RBD antibodies in pre-vaccinated mice. |
|---|---|
| Journal, issue, pages | bioRxiv, Year 2025 |
| Publish date | Aug 19, 2025 |
 Authors | Chengcheng Fan / Alexander A Cohen / Kim-Marie A Dam / Annie V Rorick / Ange-Célia I Priso Fils / Zhi Yang / Priyanthi N P Gnanapragasam / Luisa N Segovia / Kathryn E Huey-Tubman / Woohyun J Moon / Paulo J C Lin / Pamela J Bjorkman / Magnus A G Hoffmann /   |
| PubMed 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 ...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. |
 External links | bioRxiv / PubMed:40894670 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 3.8 - 4.0 Å |
| Structure data |  EMDB-71513: SARS-CoV-2 Wuhan-Hu-1/BA.1 spike heterotrimer (HT2) with 3-'down' RBDs  EMDB-71514: SARS-CoV-2 Wuhan-Hu-1/BA.1 spike heterotrimer (HT2) with 1-'up' RBD  EMDB-71515: SARS-CoV-2 Wuhan-Hu-1/BA.1/Delta spike heterotrimer (HT3) with 3-'down' RBDs  EMDB-71516: SARS-CoV-2 Wuhan-Hu-1/BA.1/Delta spike heterotrimer (HT3) with 1-'up' RBD |
| Source |
|
Severe acute respiratory syndrome coronavirus 2