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Authors: Weissman et al. 

Journal/ Pre-Print:MedRxiv Preprint 

TagsBiochemistry, Structural biology, Vaccines 

Research Highlights 

  1. The D614G mutation in the SARS-CoV-2 Spike protein is associated enhanced susceptibility to antibody-mediated neutralization, suggesting that is it not an escape mutation 

  1. Structural studies suggest that the mutation stabilizes a conformation of the receptor-binding domain (RBD) which increases its exposure on the surface of the virus 

Summary 

The D614G amino acid mutation in the SARS-CoV-2 Spike protein emerged early during the COVID-19 pandemic, quickly becoming the dominant circulating strain of the coronavirusIn this paper, Weissman and colleagues present evidence that the prevailing G614 form is actually associated with increased sensitivity to antibody neutralizationSera from animal models or patients immunized with D614-Spike is used to demonstrate that approximately 5-fold lower antibody titers are required to neutralize G614-pseudoviruses relative to D614-pseudoviruses. Structural studies indicate that D614G shifts the conformational equilibrium of the RBD towards the “1-up” state, which may lead to increased exposure of the RBD on the viral surface. 

Impact for SARS-CoV2/COVID19 research efforts 

Understand the virology of SARS-CoV2/COVID19. 

Study Type 

  • In vitro study 

Strengths and limitations of the paper 

Novelty: This study demonstrates that the D614G mutation is associated with increased sensitivity to neutralization of SARS-CoV-2 pseudoviruses in vitro. 

Standing in the field:The structural results are consistent with previous reports that this mutation stabilizes a particular conformational state of the RBD. 

Appropriate statistics: Appropriate statistical tests are used, although the results of these are indicated in the main text rather than on any figures. In Fig S1a-c, the G614 variant does not achieve 0% neutralization at the highest dilution which may contribute some error to fitting the ID50. 

Viral model used:Immunizations performed with different forms of the SARS-CoV-2 Spike protein or parts thereof (original D614 variant). Neutralization assays performed with lentiviral pseudoparticles expressing the D614 or G614 Spike protein.

Translatability:Not directly translational but suggests that vaccines targeting the Spike protein will not be negatively impacted by the D614G mutation 

Main limitations: This study uses hACE2-expressing HEK293T cells as a neutralization model and infection dynamics may be very different in respiratory cells or in animal challenge models. Only one vaccine platform was tested. No further analysis is performed on serum samples, for example characterizing antibody isotype/quantity which may be of interest to other researchers. Structural studies are performed on a soluble, furin cleavage-deficient Spike construct which may behave differently from its native form.