Discovery of ultrapotent broadly neutralizing antibodies from SARS-CoV-2 elite neutralizers
- Creators
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Vanshylla, Kanika
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Fan, Chengcheng
- Wunsch, Marie
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Poopalasingam, Nareshkumar
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Meijers, Matthijs
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Kreer, Christoph
- Kleipass, Franziska
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Ruchnewitz, Denis
- Ercanoglu, Meryem S.
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Gruell, Henning
- Münn, Friederike
- Pohl, Kai
- Janicki, Hanna
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Nolden, Tobias
- Bartl, Simone
- Stein, Saskia C.
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Augustin, Max
- Dewald, Felix
- Gieselmann, Lutz
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Schommers, Philipp
- Schulz, Thomas F.
- Sander, Leif Erik
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Koch, Manuel
- Łuksza, Marta
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Lässig, Michael
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Bjorkman, Pamela J.
- Klein, Florian
Abstract
A fraction of COVID-19 convalescent individuals mount a potent antibody response to SARS-CoV-2 with cross-reactivity to SARS-CoV-1. To uncover their humoral response in detail, we performed single B cell analysis from 10 SARS-CoV-2 elite neutralizers. We isolated and analyzed 126 monoclonal antibodies, many of which were sarbecovirus cross-reactive, with some displaying merbecovirus- and embecovirus-reactivity. Several isolated broadly neutralizing antibodies were effective against B.1.1.7, B.1.351, B.1.429, B.1.617, and B.1.617.2 variants and 19 prominent potential escape sites. Furthermore, assembly of 716,806 SARS-CoV-2 sequences predicted emerging escape variants, which were also effectively neutralized. One of these broadly neutralizing potent antibodies, R40-1G8, is a IGHV3-53 RBD-class-1 antibody. Remarkably, cryo-EM analysis revealed that R40-1G8 has a flexible binding mode, targeting both "up" and "down" conformations of the RBD. Given the threat of emerging SARS-CoV-2 variants, we demonstrate that elite neutralizers are a valuable source for isolating ultrapotent antibody candidates to prevent and treat SARS-CoV-2 infection.
Additional Information
© 2021 Elsevier Inc. Received 28 September 2021, Revised 8 November 2021, Accepted 10 December 2021, Available online 18 December 2021. We would like to thank all members of the Klein lab for helpful discussions; Clara Lehmann for critical review of this manuscript and facilitating our work with the COVID-19 outpatient unit; Petra Meyer, Nicole Riet, and Ricarda Stumpf for technical assistance; Daniela Weiland, Nadine Henn, and Susanne Salomon for project and laboratory management; Knut Elbers for support with SARS-CoV-2 spike escape variants; Ching-Lin Hsieh and Jason S. McLellan for the SARS-CoV-2 HexaPro spike construct; Michael Korenkov and the team at Boehringer Ingelheim for antibody plasmids and antibodies; Pauline Hoffman, Dr. Jost Vielmetter, and the Caltech Beckman Institute Protein Expression Center for protein expression and purification; and Dr. Songye Chen for maintaining the electron microscope. Cryo-EM was performed in the Beckman Institute Resource Center for Transmission Electron Microscope at Caltech. This work was funded by grants to M.K. (DFG FOR2722); to P.J.B. by National Institutes of Health (1P01AI138938-S1); to M. Laessig by German Research Foundation (DFG) (CRC1310); to L.E.S. from COVIM "NaFoUniMedCovid19" (FKZ: 01KX2021); to F. Klein from the German Center for Infection Research (DZIF), the DFG (CRC1279 and CRC1310), European Research Council (ERC) (ERC-StG639961), and COVIM "NaFoUniMedCovid19" (FKZ: 01KX2021). Data and code availability: All data has been included in main figures or supplementary information. SARS-CoV-2 antibody sequences are available at GenBank with accession numbers OL741060 - OL741311. The atomic coordinate and 3D EM reconstruction for SARS-CoV-2 S 6P in complex with R40-1G8 Fab has been deposited in the Protein Data Bank (PDB) with PDB ID 7SC1 and the Electron Microscopy Data Bank (EMDB) with EMDB 25008, respectively. Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request. Author contributions: Conceptualization, F. Klein and K.V.; methodology, F. Klein, K.V., M.M., C.K., D.R., and C.F.; formal analysis, K.V., C.F., M.M., C.K., M.W., N.P., F.M., K.P., and H.G.; investigation, K.V., C.F., M.W., N.P., C.K., F. Kleipass, H.J., M.S.E., D.R., H.G., T.N., S.B., M.K., F.M., and K.P.; phylogenetic analysis, M.M.; sequence analysis, C.K.; resources, S.C.S., M.A., F.D., L.G., P.S., and M. Luksza; writing – original draft, K.V. and F. Klein; writing – reviewing and editing, C.F., M.M., H.G., N.P., C.K., and M.K.; supervision; F. Klein, P.J.B., M. Laessig, T.F.S., and L.E.S.; funding acquisition, F. Klein, L.E.S., M.K., M. Laessig, and P.J.B. Declaration of interests: F. Klein, K.V., and H.G. are listed as inventors on a patent application that covers aspects of this work. F.K., C.K., and H.G. are listed as inventors on a patent application regarding neutralizing antibodies against SARS-related coronaviruses. All other authors declare no competing interests.Attached Files
Published - 1-s20-S1931312821005813-main.pdf
Supplemental Material - 1-s20-S1931312821005813-main-acc.pdf
Supplemental Material - 1-s20-S1931312821005813-mmc1.pdf
Files
Additional details
- PMCID
- PMC8683262
- Eprint ID
- 112568
- Resolver ID
- CaltechAUTHORS:20211220-495801000
- FOR2722
- Deutsche Forschungsgemeinschaft (DFG)
- 1P01AI138938-S1
- NIH
- CRC1310
- Deutsche Forschungsgemeinschaft (DFG)
- 01KX2021
- Bundesministerium für Bildung und Forschung (BMBF)
- German Center for Infection Research (DZIF)
- CRC1279
- Deutsche Forschungsgemeinschaft (DFG)
- CRC1310
- Deutsche Forschungsgemeinschaft (DFG)
- 639961
- European Research Council (ERC)
- Created
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2021-12-20Created from EPrint's datestamp field
- Updated
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2023-10-24Created from EPrint's last_modified field
- Caltech groups
- COVID-19, Division of Biology and Biological Engineering