Structure-based design of a highly stable, covalently-linked SARS-CoV-2 spike trimer with improved structural properties and immunogenicity

Eduardo Olmedillas, Colin J. Mann, Weiwei Peng, Ying-Ting Wang, Ruben Diaz Avalos, Dan Bedinger, Kristen Valentine, Norazizah Shafee, Sharon L. Schendel, Meng Yuan, Guojun Lang, Romain Rouet, Daniel Christ, Weidong Jiang, Ian A. Wilson, Tim Germann, Sujan Shresta, Joost Snijder, Erica Ollmann Saphire

Research output: Working paperPreprintAcademic

Abstract

The continued threat of SARS-CoV-2 to global health necessitates development of improved research tools and vaccines. We present an improved SARS-CoV-2 spike ectodomain, “VFLIP”, bearing five proline substitutions, a flexible cleavage site linker, and an inter-protomer disulfide bond. VFLIP displays significantly improved stability, high-yield production and retains its trimeric state without exogenous trimerization motifs. High-resolution cryo-EM and glycan profiling reveal that the VFLIP quaternary structure and glycosylation mimic the native spike on the viral surface. Further, VFLIP has enhanced affinity and binding kinetics relative to other stabilized spike proteins for antibodies in the Coronavirus Immunotherapeutic Consortium (CoVIC), and mice immunized with VFLIP exhibit potent neutralizing antibody responses against wild-type and B.1.351 live SARS-CoV-2. Taken together, VFLIP represents an improved tool for diagnostics, structural biology, antibody discovery, and vaccine design.Competing Interest StatementThe authors have declared no competing interest.
Original languageEnglish
PublisherbioRxiv
Pages1-51
DOIs
Publication statusPublished - 6 May 2021

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