Abstract
Greaney et al. develop a method to map all mutations to the SARS-CoV-2 RBD that escape antibody binding and apply this method to 10 antibodies. The resulting escape maps predict which mutations arise when virus is grown in the presence of antibody and can inform the design of antibody therapeutics.
Original language | English |
---|---|
Pages (from-to) | 44-57.e9 |
Journal | Cell Host and Microbe |
Volume | 29 |
Issue number | 1 |
DOIs | |
State | Published - Jan 13 2021 |
Keywords
- SARS-CoV-2
- antibody escape
- antigenic evolution
- deep mutational scanning
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Complete Mapping of Mutations to the SARS-CoV-2 Spike Receptor-Binding Domain that Escape Antibody Recognition. / Greaney, Allison J.; Starr, Tyler N.; Gilchuk, Pavlo; Zost, Seth J.; Binshtein, Elad; Loes, Andrea N.; Hilton, Sarah K.; Huddleston, John; Eguia, Rachel; Crawford, Katharine H.D.; Dingens, Adam S.; Nargi, Rachel S.; Sutton, Rachel E.; Suryadevara, Naveenchandra; Rothlauf, Paul W.; Liu, Zhuoming; Whelan, Sean P.J.; Carnahan, Robert H.; Crowe, James E.; Bloom, Jesse D.
In: Cell Host and Microbe, Vol. 29, No. 1, 13.01.2021, p. 44-57.e9.Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Complete Mapping of Mutations to the SARS-CoV-2 Spike Receptor-Binding Domain that Escape Antibody Recognition
AU - Greaney, Allison J.
AU - Starr, Tyler N.
AU - Gilchuk, Pavlo
AU - Zost, Seth J.
AU - Binshtein, Elad
AU - Loes, Andrea N.
AU - Hilton, Sarah K.
AU - Huddleston, John
AU - Eguia, Rachel
AU - Crawford, Katharine H.D.
AU - Dingens, Adam S.
AU - Nargi, Rachel S.
AU - Sutton, Rachel E.
AU - Suryadevara, Naveenchandra
AU - Rothlauf, Paul W.
AU - Liu, Zhuoming
AU - Whelan, Sean P.J.
AU - Carnahan, Robert H.
AU - Crowe, James E.
AU - Bloom, Jesse D.
N1 - Funding Information: The remaining antibodies target several regions on the RBM: four antibodies are escaped by mutations on the internal or external face of one lateral edge of the RBM (the ?ACE2-binding ridge,? Figure 4B), one antibody is escaped by mutations on the external face at the opposite edge of the RBM (Figure 4C), and one antibody is escaped by mutations that bridge the external surface of the central concave ?saddle? of the RBM (Figure 4D). In all cases, the escape mutations fall in or near the structurally defined contact surface between the antibody and RBD (Figures 4E and 4F). In some cases, the negative-stain EM explains features of the escape-mutant maps (Figure 4F). For instance, COV2-2165 is escaped by mutations at site D420 in addition to the ACE2-binding ridge, suggesting a binding footprint that extends beyond the ACE2-binding ridge. This hypothesis is supported by negative-stain EM data, which shows differences in the binding approach of COV2-2165 relative to that of COV2-2832, another ACE2-binding ridge antibody that is not escaped by mutations at D420 (Figure 4F).We thank Keara Malone for experimental assistance; Mike Murphy and Neil King for rCR3022 protein; and the FHCRC Flow Cytometry and Genomics core facilities for experimental support, especially Dolores Covarrubias, Andy Marty, and MinJae Kim. EM data collections were conducted at the Center for Structural Biology Cryo-EM Facility at VU. This work was supported by the NIAID / NIH (R01AI141707 and R01AI127893 to J.D.B. T32AI083203 to A.J.G. T32AI095202 to S.J.Z. and F30AI149928 to K.H.D.C.); the Gates Foundation (INV-004949); DARPA (HR0011-18-2-0001 and HR0011-18-3-0001); NIH contracts (75N93019C00074 and 75N93019C00062); NIH grants (U01AI150739, R01AI130591, and R35HL145242); the Dolly Parton COVID-19 Research Fund at Vanderbilt; and Fast Grants, Mercatus Center, George Mason University. T.N.S. is an HHMI Damon Runyon Cancer Research Foundation Fellow (DRG-2381-19). J.E.C. is a recipient of the 2019 Future Insight Prize from Merck KGaA. J.D.B. is an HHMI Investigator. The content is solely the responsibility of the authors and does not represent the official views of the US government or other sponsors. Conceptualization, A.J.G. T.N.S. S.Z. J.E.C. and J.D.B.; Methodology, A.J.G. T.N.S. S.Z. E.B. P.G. R.S.N. R.E.S. N.S. P.W.R. Z.L. S.P.J.W. R.H.C. and J.D.B.; Investigation, A.J.G. T.N.S. S.Z. P.G. and E.B.; Code, A.J.G. T.N.S. and J.D.B.; Formal Analysis, A.J.G. T.N.S. and J.D.B.; Validation, A.J.G. A.N.L. R.E. and K.H.D.C.; Writing Original Draft, A.J.G. T.N.S. and J.D.B.; Review and Editing, all authors; Supervision, J.E.C. and J.D.B. J.E.C. has served as a consultant for Sanofi, is on the Scientific Advisory Boards of CompuVax and Meissa Vaccines, is a recipient of previous unrelated grants from Moderna and Sanofi, and is a founder of IDBiologics. Vanderbilt University has applied for patents on SARS-CoV-2 antibodies. S.P.J.W. and P.W.R. have filed a disclosure with Washington University for recombinant VSV. The other authors declare no competing interests. Funding Information: We thank Keara Malone for experimental assistance; Mike Murphy and Neil King for rCR3022 protein; and the FHCRC Flow Cytometry and Genomics core facilities for experimental support, especially Dolores Covarrubias, Andy Marty, and MinJae Kim. EM data collections were conducted at the Center for Structural Biology Cryo-EM Facility at VU. This work was supported by the NIAID / NIH ( R01AI141707 and R01AI127893 to J.D.B., T32AI083203 to A.J.G., T32AI095202 to S.J.Z., and F30AI149928 to K.H.D.C.); the Gates Foundation ( INV-004949 ); DARPA ( HR0011-18-2-0001 and HR0011-18-3-0001 ); NIH contracts ( 75N93019C00074 and 75N93019C00062 ); NIH grants ( U01AI150739 , R01AI130591 , and R35HL145242 ); the Dolly Parton COVID-19 Research Fund at Vanderbilt; and Fast Grants , Mercatus Center , George Mason University . T.N.S. is an HHMI Damon Runyon Cancer Research Foundation Fellow ( DRG-2381-19 ). J.E.C. is a recipient of the 2019 Future Insight Prize from Merck KGaA. J.D.B. is an HHMI Investigator. The content is solely the responsibility of the authors and does not represent the official views of the US government or other sponsors. Publisher Copyright: © 2020 The Authors
PY - 2021/1/13
Y1 - 2021/1/13
N2 - Greaney et al. develop a method to map all mutations to the SARS-CoV-2 RBD that escape antibody binding and apply this method to 10 antibodies. The resulting escape maps predict which mutations arise when virus is grown in the presence of antibody and can inform the design of antibody therapeutics.
AB - Greaney et al. develop a method to map all mutations to the SARS-CoV-2 RBD that escape antibody binding and apply this method to 10 antibodies. The resulting escape maps predict which mutations arise when virus is grown in the presence of antibody and can inform the design of antibody therapeutics.
KW - SARS-CoV-2
KW - antibody escape
KW - antigenic evolution
KW - deep mutational scanning
UR - http://www.scopus.com/inward/record.url?scp=85097068093&partnerID=8YFLogxK
U2 - 10.1016/j.chom.2020.11.007
DO - 10.1016/j.chom.2020.11.007
M3 - Article
C2 - 33259788
AN - SCOPUS:85097068093
VL - 29
SP - 44-57.e9
JO - Cell Host and Microbe
JF - Cell Host and Microbe
SN - 1931-3128
IS - 1
ER -