3 July 2024 | Bernadeta Dadonaite, Jack Brown, Teagan E. McMahon, Ariana G. Farrell, Martin D. Figgins, Daniel Asarnow, Cameron Stewart, Jimin Lee, Jenni Logue, Trevor Bedford, Ben Murrell, Helen Y. Chu, David Veesler, Jesse D. Bloom
This study uses pseudovirus deep mutational scanning to measure the effects of over 9,000 mutations across the XBB.1.5 and BA.2 spike proteins on three critical viral fitness traits: ACE2 binding, cell entry, and neutralization by human sera. The results show that mutations outside the receptor-binding domain (RBD) can significantly affect ACE2 binding, and that the strongest serum escape mutations are located within the RBD at sites 357, 420, 440, 456, and 473. However, many of these mutations also decrease ACE2 binding, suggesting they act by modulating RBD conformation. The study also identifies strong escape mutations outside the RBD, some of which decrease ACE2 binding. Notably, the growth rates of human SARS-CoV-2 clades can be explained in part by the measured effects of mutations on these spike phenotypes, indicating that deep mutational scanning could enable better prediction of viral evolution. The findings highlight the importance of non-RBD mutations in SARS-CoV-2 evolution and provide insights into the mechanisms of immune evasion and viral fitness.This study uses pseudovirus deep mutational scanning to measure the effects of over 9,000 mutations across the XBB.1.5 and BA.2 spike proteins on three critical viral fitness traits: ACE2 binding, cell entry, and neutralization by human sera. The results show that mutations outside the receptor-binding domain (RBD) can significantly affect ACE2 binding, and that the strongest serum escape mutations are located within the RBD at sites 357, 420, 440, 456, and 473. However, many of these mutations also decrease ACE2 binding, suggesting they act by modulating RBD conformation. The study also identifies strong escape mutations outside the RBD, some of which decrease ACE2 binding. Notably, the growth rates of human SARS-CoV-2 clades can be explained in part by the measured effects of mutations on these spike phenotypes, indicating that deep mutational scanning could enable better prediction of viral evolution. The findings highlight the importance of non-RBD mutations in SARS-CoV-2 evolution and provide insights into the mechanisms of immune evasion and viral fitness.