SARS-CoV-2 spike conformation determines plasma neutralizing activity

Bowen, J. E.; Walls, A. C.; Joshi, A.; Sprouse, K. R.; Stewart, C.; Tortorici, M. A.; Franko, N. M.; Logue, J. K.; Mazzitelli, I. G.; Tiles, S. W.; Ahmed, K.; Shariq, A.; Snell, G.; Iqbal, N. T.; Geffner, J.; Bandera, A.; Gori, A.; Grifantini, R.; Chu, H. Y.; Van Voorhis, W. C.; Corti, D.; Veesler, D.

doi:10.1101/2021.12.19.473391

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bioRxiv · 10.1101/2021.12.19.473391

SARS-CoV-2 spike conformation determines plasma neutralizing activity

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Abstract

Numerous safe and effective COVID-19 vaccines have been developed that utilize various delivery technologies and engineering strategies. The influence of the SARS-CoV-2 spike (S) glycoprotein conformation on antibody responses induced by vaccination or infection in humans remains unknown. To address this question, we compared plasma antibodies elicited by six globally-distributed vaccines or infection and observed markedly higher binding titers for vaccines encoding a prefusion-stabilized S relative to other groups. Prefusion S binding titers positively correlated with plasma neutralizing activity, indicating that physical stabilization of the prefusion conformation enhances protection against SARS-CoV-2. We show that almost all plasma neutralizing activity is directed to prefusion S, in particular the S1 subunit, and that variant cross-neutralization is mediated solely by RBD-specific antibodies. Our data provide a quantitative framework for guiding future S engineering efforts to develop vaccines with higher resilience to the emergence of variants and longer durability than current technologies.

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Bowen, J. E., Walls, A. C., Joshi, A., Sprouse, K. R., Stewart, C., Tortorici, M. A., Franko, N. M., Logue, J. K., Mazzitelli, I. G., Tiles, S. W., Ahmed, K., Shariq, A., Snell, G., Iqbal, N. T., Geffner, J., Bandera, A., Gori, A., Grifantini, R., Chu, H. Y., Van Voorhis, W. C., Corti, D., Veesler, D.. 2021-12-21. SARS-CoV-2 spike conformation determines plasma neutralizing activity. https://doi.org/10.1101/2021.12.19.473391

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