Cell
Volume 186, Issue 11, 25 May 2023, Pages 2380-2391.e9
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Article
ESCRT recruitment to SARS-CoV-2 spike induces virus-like particles that improve mRNA vaccines

https://doi.org/10.1016/j.cell.2023.04.024Get rights and content
Under a Creative Commons license
open access

Highlights

  • EABR technology engineers membrane proteins to induce assembly of enveloped VLPs

  • SARS-CoV-2 spike-EABR eVLPs were genetically encoded and delivered as mRNA vaccine

  • Spike-EABR mRNA elicits higher antibody titers than conventional spike mRNA in mice

  • Spike-EABR mRNA elicits potent antibody responses against Omicron variants

Summary

Prime-boost regimens for COVID-19 vaccines elicit poor antibody responses against Omicron-based variants and employ frequent boosters to maintain antibody levels. We present a natural infection-mimicking technology that combines features of mRNA- and protein nanoparticle-based vaccines through encoding self-assembling enveloped virus-like particles (eVLPs). eVLP assembly is achieved by inserting an ESCRT- and ALIX-binding region (EABR) into the SARS-CoV-2 spike cytoplasmic tail, which recruits ESCRT proteins to induce eVLP budding from cells. Purified spike-EABR eVLPs presented densely arrayed spikes and elicited potent antibody responses in mice. Two immunizations with mRNA-LNP encoding spike-EABR elicited potent CD8+ T cell responses and superior neutralizing antibody responses against original and variant SARS-CoV-2 compared with conventional spike-encoding mRNA-LNP and purified spike-EABR eVLPs, improving neutralizing titers >10-fold against Omicron-based variants for 3 months post-boost. Thus, EABR technology enhances potency and breadth of vaccine-induced responses through antigen presentation on cell surfaces and eVLPs, enabling longer-lasting protection against SARS-CoV-2 and other viruses.

Keywords

nanoparticles
mRNA vaccines
SARS-CoV-2
ESCRT

Data and code availability

All data are available in the main text or the supplemental information. Materials are available upon request to the corresponding authors with a signed material transfer agreement. Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request. This paper does not report original code. This work is licensed under a Creative Commons Attribution 4.0 International (CC BY 4.0) license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/. This license does not apply to figures/photos/artwork or other content included in the article that is credited to a third party; obtain authorization from the rights holder before using such material.

Cited by (0)

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Present address: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA

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Lead contact