Enhanced Omicron subvariant cross-neutralization efficacy of a monovalent SARS-CoV-2 BA.4/5 mRNA vaccine encoding a noncleaved, nonfusogenic spike antigen

Seo, H. Y.; Jung, H.; Woo, H.; Jung, H.-G.; Bak, Y.; Lee, S.-Y.; Son, Y.-M.; Yoon, G.; Hwang, S.-Y.; Park, I.; Shin, J.-S.; Oh, J.-W.

doi:10.1101/2023.09.10.557088

bioRxiv · 10.1101/2023.09.10.557088

Enhanced Omicron subvariant cross-neutralization efficacy of a monovalent SARS-CoV-2 BA.4/5 mRNA vaccine encoding a noncleaved, nonfusogenic spike antigen

Seo, H. Y.·Jung, H.·Woo, H.·Jung, H.-G.·Bak, Y.·Lee, S.-Y.·Son, Y.-M.·Yoon, G.·Hwang, S.-Y.·Park, I.·Shin, J.-S.·Oh, J.-W.

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Abstract

The rapid emergence of diverse SARS-CoV-2 variants, notably the Omicron variant, poses challenges to vaccine development. Here, we present a noncleaved, nonfusogenic spike (S) protein eliciting robust B- and T-cell immune responses against Omicron BA.5. The antigen incorporates the R685S and R815A mutations, effectively preventing the shedding of the S1 subunit and eliminating fusogenic activity of the resulting S antigen, termed S(SA). Through reverse genetic analysis, we found that the noncleaved form S protein with the R685S mutation enhances ACE2-dependent viral entry in vitro compared to the wild-type S protein, without increasing the virulence of the mutant virus in mice. The mRNA vaccine encoding the Omicron BA.4/5 S(SA) antigen conferred protective immunity in mice following two doses of 1 g {Psi}-UTP- or UTP-incorporated mRNA vaccines. Despite a roughly 6-fold reduction in neutralizing potency, both mRNA vaccines exhibited broad neutralizing efficacy against Omicron subvariants, including the XBB lineage variants XBB.1.5 and XBB.1.16.

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Seo, H. Y., Jung, H., Woo, H., Jung, H.-G., Bak, Y., Lee, S.-Y., Son, Y.-M., Yoon, G., Hwang, S.-Y., Park, I., Shin, J.-S., Oh, J.-W.. 2023-09-11. Enhanced Omicron subvariant cross-neutralization efficacy of a monovalent SARS-CoV-2 BA.4/5 mRNA vaccine encoding a noncleaved, nonfusogenic spike antigen. https://doi.org/10.1101/2023.09.10.557088

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