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Structure of a germline-like human antibody defines a neutralizing epitope on the SARS-CoV-2 spike NTD

By Clara Gilda Altomare, Daniel Cole Adelsberg, Juan Manuel Carreno, Iden Avery Sapse, Fatima Amanat, Ali Ellebedy, Viviana Simon, Florian Krammer, Goran Bajic

Posted 08 Jul 2021
bioRxiv DOI: 10.1101/2021.07.08.451649

Structural characterization of infection- and vaccination-elicited antibodies in complex with antigen provides insight into the evolutionary arms race between the host and the pathogen and informs rational vaccine immunogen design. We isolated a germline-like monoclonal antibody (mAb) from plasmablasts activated upon mRNA vaccination against SARS-CoV-2 and determined its structure in complex with the spike glycoprotein by cryo-EM. We show that the mAb engages a previously uncharacterized neutralizing epitope on the spike N-terminal domain (NTD). The high-resolution structure reveals details of the intermolecular interactions and shows that the mAb inserts its HCDR3 loop into a hydrophobic NTD cavity previously shown to bind a heme metabolite, biliverdin. We demonstrate direct competition with biliverdin and that - because of the conserved nature of the epitope - the mAb maintains binding to viral variants B.1.1.7 and B.1.351. Our study illustrates the feasibility of targeting the NTD to achieve broad neutralization against SARS-CoV-2 variants.

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