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

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 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 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.

The SARS-CoV-2 and other human coronavirus spike proteins are fine-tuned towards temperature and proteases of the human airways

“…Improved stability may be the reason why SARS-CoV-2-S D614 was superseded by the S G614 variant within a few months of circulation in humans (43). Animal studies showed that the SARS-CoV-2-S G614 variant has higher fitness and transmissibility (40)(41)(42). This is reminiscent of influenza virus, for which the link between hemagglutinin stability and transmissibility is well established (13,68).…”

“…Within a few months circulation among humans, SARS-CoV-2 has acquired a mutation (D614G) in its spike protein, that is increasingly recognized as a possible cause of enhanced virus transmission (40)(41)(42). The D614G mutation was already detected during the early phase of the pandemic and, after four months, the S G614 variant became globally predominant (43).…”

“…The D614G mutation was already detected during the early phase of the pandemic and, after four months, the S G614 variant became globally predominant (43). Compared to SARS-CoV-2-S D614 virus, the S G614 variant exhibits higher transmissibility in animal models (40)(41)(42). The D614G mutation was also shown to enhance SARS-CoV-2 replication (40)(41)(42) and increase infectivity of SARS-2-S-bearing pseudoparticles (40,42,(44)(45)(46)(47).…”

Community Transmission of SARS-CoV-2 by Surfaces: Risks and Risk Reduction Strategies

“…The upper bounds of the dose–response curve are consistent with the infectivity of two different variants of SARS-CoV-2 in mice, hamsters, and ferrets, which showed 100% infectivity at a dose of 10 5 TCID 50 . 46 Monte Carlo simulations were used to incorporate the uncertainty and variability of the input parameters. The model was simulated 50,000 times.…”

A Gapless, Unambiguous RNA Metagenome-Assembled Genome Sequence of a Unique SARS-CoV-2 Variant Encoding Spike S813I and ORF1a A859V Substitutions

“…Numerous reports focused on the spike D614G variation (Díez-Fuertes et al, 2020;Korber et al, 2020;Plante et al, 2020;Zhou et al, 2020). Although it is not the most frequent variation, it is quite prevalent, and its occurrence in the spike protein made it an attractive target for speculations about an effect on viral transmissibility, infection efficiency, virulence, immunogenicity, immune evasion, and even disease prognosis (Grubaugh et al, 2020;Hou et al, 2020;Korber et al, 2020;Zhou et al, 2020). Yet, the only solid experimental evidence supports a slightly higher transmissibility but no significant structural effects leading to virulence or immune evasion (Díez-Fuertes et al, 2020;Grubaugh et al, 2020;Korber et al, 2020;Plante et al, 2020).…”