SARS-CoV-2 spike D614G variant confers enhanced replication and transmissibility

Zhou, B.; Thao, T. T. N.; Hoffmann, D.; Taddeo, A.; Ebert, N.; Labroussaa, F.; Pohlmann, A.; King, J.; Portmann, J.; Halwe, N. J.; Ulrich, L.; Trueb, B. S.; Kelly, J. N.; Fan, X.; Hoffmann, B.; Steiner, S.; Wang, L.; Thomann, L.; Lin, X.; Stalder, H.; Pozzi, B.; de Brot, S.; Jiang, N.; Cui, D.; Hossain, J.; Wilson, M.; Keller, M. W.; Stark, T. J.; Barnes, J. R.; Dijkman, R.; Jores, J.; Benarafa, C.; Wentworth, D. E.; Thiel, V.; Beer, M.

doi:10.1101/2020.10.27.357558

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bioRxiv · 10.1101/2020.10.27.357558

SARS-CoV-2 spike D614G variant confers enhanced replication and transmissibility

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Abstract

During the evolution of SARS-CoV-2 in humans a D614G substitution in the spike (S) protein emerged and became the predominant circulating variant (S-614G) of the COVID-19 pandemic1. However, whether the increasing prevalence of the S-614G variant represents a fitness advantage that improves replication and/or transmission in humans or is merely due to founder effects remains elusive. Here, we generated isogenic SARS-CoV-2 variants and demonstrate that the S-614G variant has (i) enhanced binding to human ACE2, (ii) increased replication in primary human bronchial and nasal airway epithelial cultures as well as in a novel human ACE2 knock-in mouse model, and (iii) markedly increased replication and transmissibility in hamster and ferret models of SARS-CoV-2 infection. Collectively, our data show that while the S-614G substitution results in subtle increases in binding and replication in vitro, it provides a real competitive advantage in vivo, particularly during the transmission bottle neck, providing an explanation for the global predominance of S-614G variant among the SARS-CoV-2 viruses currently circulating.

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Zhou, B., Thao, T. T. N., Hoffmann, D., Taddeo, A., Ebert, N., Labroussaa, F., Pohlmann, A., King, J., Portmann, J., Halwe, N. J., Ulrich, L., Trueb, B. S., Kelly, J. N., Fan, X., Hoffmann, B., Steiner, S., Wang, L., Thomann, L., Lin, X., Stalder, H., Pozzi, B., de Brot, S., Jiang, N., Cui, D., Hossain, J., Wilson, M., Keller, M. W., Stark, T. J., Barnes, J. R., Dijkman, R., Jores, J., Benarafa, C., Wentworth, D. E., Thiel, V., Beer, M.. 2020-10-27. SARS-CoV-2 spike D614G variant confers enhanced replication and transmissibility. https://doi.org/10.1101/2020.10.27.357558

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