Thread by @veeslerlab

Delighted to share our study of the #SARSCoV2 E406W spike mutant describing how a single amino acid mutation mediates escape from the REGN10987/REGN10933 antibody cocktail despite residing outside their epitopes

Led by @AminAddetia

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biorxiv.org/content/10.110…

The E406W mutation was previously described by @tylernstarr @AllieGreaney (along with @AminAddetia during his rotation in) @jbloom_lab using deep-mutational scanning and neutralization assays.

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science.org/doi/10.1126/sc…

We determined a #CryoEM structure of the E406W spike trimer and observed a remodeling of the receptor-binding domain (RBD), hindering binding of clinical antibodies such as the REGN10987/REGN10933 cocktail or COV2-2130

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We show that the structural reorganization of the RBD dampens recognition of the ACE2 receptor severely (~14x) relative to the Wuhan-Hu-1 RBD, which suggests there would be a fitness cost for such a virus.

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mRNA vaccine-elicited neutralizing antibody titers are decreased ~2.5-fold against the E406W mutant, to levels similar to the ones against Delta or Epsilon #SARSCoV2 variants, which is impressive for a single point mutation!

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Good news is that broadly neutralizing sarbecovirus monoclonal antibodies, such as S2E12, S2X259 and the clinical S309 (sotrovimab) are unaffected by this mutation, indicating several strategies are available should a E406W mutant virus emerge in the future.

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E406W requires multiple nucleotide substitutions from the Wuhan-Hu-1 spike, has a strong deleterious effect on ACE2 binding and has not been detected in clinical isolates but illustrates the structural and functional plasticity of the SARS-CoV-2 RBD

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Thank you so much @YoungjunPark11 @tylernstarr @AllieGreaney @sprouse_kaitlin @johnbowenbio @jbloom_lab @DavideCorti6 @coronalexington & all other collaborators!

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