Spike deep mutational scanning helps predict success of SARS-CoV-2 clades

Bernadeta Dadonaite, Jack Brown, Teagan E. McMahon, Ariana G. Farrell, Marlin D. Figgins, Daniel Asarnow, Cameron Stewart, Jimin Lee, Jenni Logue, Trevor Bedford, Ben Murrell, Helen Y. Chu, David Veesler and Jesse D. Bloom ()
Additional contact information
Bernadeta Dadonaite: Fred Hutchinson Cancer Center
Jack Brown: University of Washington
Teagan E. McMahon: Fred Hutchinson Cancer Center
Ariana G. Farrell: Fred Hutchinson Cancer Center
Marlin D. Figgins: Fred Hutchinson Cancer Center
Daniel Asarnow: University of Washington
Cameron Stewart: University of Washington
Jimin Lee: University of Washington
Jenni Logue: Division of Allergy and Infectious Diseases
Trevor Bedford: Fred Hutchinson Cancer Center
Ben Murrell: Karolinska Institutet
Helen Y. Chu: Division of Allergy and Infectious Diseases
David Veesler: University of Washington
Jesse D. Bloom: Fred Hutchinson Cancer Center

Nature, 2024, vol. 631, issue 8021, 617-626

Abstract: Abstract SARS-CoV-2 variants acquire mutations in the spike protein that promote immune evasion1 and affect other properties that contribute to viral fitness, such as ACE2 receptor binding and cell entry2,3. Knowledge of how mutations affect these spike phenotypes can provide insight into the current and potential future evolution of the virus. Here we use pseudovirus deep mutational scanning4 to measure how more than 9,000 mutations across the full XBB.1.5 and BA.2 spikes affect ACE2 binding, cell entry or escape from human sera. We find that mutations outside the receptor-binding domain (RBD) have meaningfully affected ACE2 binding during SARS-CoV-2 evolution. We also measure how mutations to the XBB.1.5 spike affect neutralization by serum from individuals who recently had SARS-CoV-2 infections. The strongest serum escape mutations are in the RBD at sites 357, 420, 440, 456 and 473; however, the antigenic effects of these mutations vary across individuals. We also identify strong escape mutations outside the RBD; however, many of them decrease ACE2 binding, suggesting they act by modulating RBD conformation. Notably, the growth rates of human SARS-CoV-2 clades can be explained in substantial part by the measured effects of mutations on spike phenotypes, suggesting our data could enable better prediction of viral evolution.

Date: 2024
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DOI: 10.1038/s41586-024-07636-1

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