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

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

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(1). 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.