ESCRT recruitment to mRNA-encoded SARS-CoV-2 spike induces virus-like particles and enhanced antibody responses

Hoffmann, M. A.; Yang, Z.; Huey-Tubman, K. E.; Cohen, A. A.; Gnanapragasam, P. N.; Nakatomi, L. M.; Storm, K. N.; Moon, W. J.; Lin, P. J.; Bjorkman, P. J.

doi:10.1101/2022.12.26.521940

bioRxiv · 10.1101/2022.12.26.521940

ESCRT recruitment to mRNA-encoded SARS-CoV-2 spike induces virus-like particles and enhanced antibody responses

Hoffmann, M. A.·Yang, Z.·Huey-Tubman, K. E.·Cohen, A. A.·Gnanapragasam, P. N.·Nakatomi, L. M.·Storm, K. N.·Moon, W. J.·Lin, P. J.·Bjorkman, P. J.

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Abstract

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 to conventional spike-encoding mRNA-LNP and purified spike-EABR eVLPs, improving neutralizing titers >10-fold against Omicron-based variants for three 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.

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Hoffmann, M. A., Yang, Z., Huey-Tubman, K. E., Cohen, A. A., Gnanapragasam, P. N., Nakatomi, L. M., Storm, K. N., Moon, W. J., Lin, P. J., Bjorkman, P. J.. 2022-12-27. ESCRT recruitment to mRNA-encoded SARS-CoV-2 spike induces virus-like particles and enhanced antibody responses. https://doi.org/10.1101/2022.12.26.521940

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