SARS-CoV-2 spike D614G change enhances replication and transmission

Bin Zhou, Tran Thi Nhu Thao, Donata Hoffmann, Adriano Taddeo, Nadine Ebert, Fabien Labroussaa, Anne Pohlmann, Jacqueline King, Silvio Steiner, Jenna N. Kelly, Jasmine Portmann, Nico Joel Halwe, Lorenz Ulrich, Bettina Salome Trüeb, Xiaoyu Fan, Bernd Hoffmann, Li Wang, Lisa Thomann, Xudong Lin, Hanspeter Stalder, Berta Pozzi, Simone de Brot, Nannan Jiang, Dan Cui, Jaber Hossain, Malania Wilson, Matthew Keller, Thomas J. Stark, John R. Barnes, Ronald Dijkman, Joerg Jores, Charaf Benarafa, David E. Wentworth, Volker Thiel & Martin Beer

*These authors contributed equally; &These authors jointly supervised this work

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 pandemic. 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 host cell surface receptor angiotensin-converting enzyme 2 (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.

Published February 2021 in Nature

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HONOURs

Host switching pathogens, infectious outbreaks and zoonosis; a Marie Sklodowska-Curie Innovative Training Network.

This project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 721367.