Structural Basis for Potent Neutralization of Betacoronaviruses by Single-Domain Camelid Antibodies
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Abstract
Coronaviruses make use of a large envelope protein called spike (S) to engage host cell receptors and catalyze membrane fusion. Because of the vital role that these S proteins play, they represent a vulnerable target for the development of therapeutics. Here, we describe the isolation of single-domain antibodies (VHHs) from a llama immunized with prefusion-stabilized coronavirus spikes. These VHHs neutralize MERS-CoV or SARS-CoV-1 S pseudotyped viruses, respectively. Crystal structures of these VHHs bound to their respective viral targets reveal two distinct epitopes, but both VHHs interfere with receptor binding. We also show cross-reactivity between the SARS-CoV-1 S-directed VHH and SARS-CoV-2 S and demonstrate that this cross-reactive VHH neutralizes SARS-CoV-2 S pseudotyped viruses as a bivalent human IgG Fc-fusion. These data provide a molecular basis for the neutralization of pathogenic betacoronaviruses by VHHs and suggest that these molecules may serve as useful therapeutics during coronavirus outbreaks.
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S-2P conformational stability translates into greater immunogenicity, based on preservation of neutralization-sensitive epitopes and improved protein expression.
“Moreover, S-2P conformational stability translates into greater immunogenicity,27-29 based on preservation of neutralization-sensitive epitopes at the apex of the prefusion molecule, as shown for respiratory syncytial virus F glycoprotein,30 and improved protein expression,27 which is particularly advantageous for gene-based antigen delivery.”
From An mRNA Vaccine against SARS-CoV-2 — Preliminary Report (2020) · cites this paper as [28]
The Introduction and Discussion report that immunization with prefusion-stabilized SARS-CoV-1 and MERS-CoV spikes elicited neutralizing antibodies. They do not compare S-2P immunogenicity with an unstabilized spike or show that S-2P stability improved protein expression; the expression yield reported in the Discussion is for the engineered VHH-72-Fc antibody, not S-2P. No page numbers are available in our copy. (LLM, conf=0.84)
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Cites
Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation
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- Authors
- Wrapp, D., De Vlieger, D., Corbett, K. S., Torres, G. M., Wang, N., Van Breedam, W., Roose, K., van Schie, L., Hoffmann, M., Pöhlmann, S., Graham, B. S., Callewaert, N., Schepens, B., Saelens, X., & McLellan, J. S.
- Affiliations
- The University of Texas at Austin (US)
- National Institutes of Health (US)
- Dartmouth College (US)
- Ghent University (BE)
- German Primate Center (DE)
- Corresponding author
- Schepens, Bert
- Saelens, Xavier
- McLellan, Jason S.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2020-05
- Volume
- 181
- Issue
- 5
- Pages
- 1004-1015.e15
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC7199733
- OpenAlex
- W3017133925
- Cited by
- 610
- References
- 6
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- en
- Update notices
- erratum (2020-06-11)
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (am, 392 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (acceptedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nd)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Ghent University Academic Bibliography (Ghent University) (publishedVersion, other-oa)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases
- Topics
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
- Life Sciences › Agricultural and Biological Sciences › Animal Science and Zoology › Animal Virus Infections Studies
- Keywords
- nanobodies, VHH, betacoronaviruses, SARS-CoV-1, SARS-CoV-2, MERS-CoV, spike protein, neutralizing antibodies, receptor binding, epitope mapping, cross-reactivity, Fc fusion, camelid antibodies, coronavirus therapeutics
- MeSH terms
- Protein Domains, Betacoronavirus, COVID-19, SARS-CoV-2, Animals, Camelids, New World, Cross Reactions, Immunoglobulin G, Models, Molecular, Pneumonia, Viral, Receptors, Virus, Coronavirus Infections, Antibodies, Neutralizing, Pandemics, Single-Domain Antibodies, Spike Glycoprotein, Coronavirus
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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