@article{7f7cf1d832874aff881e9d560cf2a84a,
title = "Antibody escape and cryptic cross-domain stabilization in the SARS-CoV-2 Omicron spike protein",
abstract = "The worldwide spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to the repeated emergence of variants of concern. For the Omicron variant, sub-lineages BA.1 and BA.2, respectively, contain 33 and 29 nonsynonymous and indel spike protein mutations. These amino acid substitutions and indels are implicated in increased transmissibility and enhanced immune evasion. By reverting individual spike mutations of BA.1 or BA.2, we characterize the molecular effects of the Omicron spike mutations on expression, ACE2 receptor affinity, and neutralizing antibody recognition. We identified key mutations enabling escape from neutralizing antibodies at a variety of epitopes. Stabilizing mutations in the N-terminal and S2 domains of the spike protein can compensate for destabilizing mutations in the receptor binding domain, enabling the record number of mutations in Omicron. Our results provide a comprehensive account of the mutational effects in the Omicron spike protein and illustrate previously uncharacterized mechanisms of host evasion.",
keywords = "COVID-19, VOCs, cell display, flow cytometry, high throughput, viral glycoprotein, SARS-CoV-2/genetics, Antibodies, Neutralizing/genetics, Humans, Viral Envelope Proteins, Epitopes, Antibodies, Viral, Angiotensin-Converting Enzyme 2/genetics, Spike Glycoprotein, Coronavirus/genetics, Membrane Glycoproteins, Mutation",
author = "Kamyab Javanmardi and Segall-Shapiro, {Thomas H.} and Chou, {Chia Wei} and Boutz, {Daniel R.} and Olsen, {Randall J.} and Xuping Xie and Hongjie Xia and Shi, {Pei Yong} and Johnson, {Charlie D.} and Ankur Annapareddy and Scott Weaver and Musser, {James M.} and Ellington, {Andrew D.} and Finkelstein, {Ilya J.} and Gollihar, {Jimmy D.}",
note = "Funding Information: We thank Dr. Sasha M. Pejerrey, Dr. Heather McConnell, and Ms. Adrienne Winston for editorial contributions. The research was supported in part by the Houston Methodist Academic Institute Infectious Diseases Fund and many generous Houston philanthropists (J.M.M. and J.D.G.). We are grateful to Carole Walter Looke and Jim Looke for their generous philanthropic gift to ADAPT (J.D.G.). The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. K.J. was supported by the Provost{\textquoteright}s Graduate Excellence Fellowship (PGEF) at UT Austin. C.D.J. was supported by the P2P-TEAM Program (1T32GM139796-01). The research was also supported by a Cooperative Agreement ( W911NF-17-2-0091 ) between ARL and UT Austin to A.D.E. and J.D.G., the Bill and Melinda Gates Foundation (K.J., C.-W.C, A.A., and I.J.F.), and the Welch Foundation ( F-1808 to I.J.F., F-1655 to A.D.E.). Funding Information: We thank Dr. Sasha M. Pejerrey, Dr. Heather McConnell, and Ms. Adrienne Winston for editorial contributions. The research was supported in part by the Houston Methodist Academic Institute Infectious Diseases Fund and many generous Houston philanthropists (J.M.M. and J.D.G.). We are grateful to Carole Walter Looke and Jim Looke for their generous philanthropic gift to ADAPT (J.D.G.). The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. K.J. was supported by the Provost's Graduate Excellence Fellowship (PGEF) at UT Austin. C.D.J. was supported by the P2P-TEAM Program (1T32GM139796-01). The research was also supported by a Cooperative Agreement (W911NF-17-2-0091) between ARL and UT Austin to A.D.E. and J.D.G. the Bill and Melinda Gates Foundation (K.J. C.-W.C, A.A. and I.J.F.), and the Welch Foundation (F-1808 to I.J.F. F-1655 to A.D.E.). K.J. T.H.S.-S. I.J.F. and J.D.G. designed the research. K.J. performed the flow experiments. K.J. D.R.B. A.A. and J.D.G. purified antibodies and other reagents. K.J. and T.H.S.-S. cloned spike variants. K.J. and C.-W.C. performed BLI and DSF experiments. R.J.O. and J.M.M. isolated and sequenced Omicron. X.X. H.X. P.-Y.S. and S.W. provided the authentic virus neutralization data. K.J. T.H.S.-S. C.D.J. and J.D.G. analyzed the data. K.J. T.H.S.-S. A.D.E. I.J.F. and J.D.G. wrote the paper with editorial assistance from all co-authors. D.R.B. A.D.E. and J.D.G. have filed patent applications monoclonal antibodies targeting SARS-CoV-2. K.J. C.-W.C. and I.J.F. have filed patent applications on spike 6p (HexaPro). One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in science. The author list of this paper includes contributors from the location where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work. Publisher Copyright: {\textcopyright} 2022 Elsevier Inc.",
year = "2022",
month = sep,
day = "14",
doi = "10.1016/j.chom.2022.07.016",
language = "English (US)",
volume = "30",
pages = "1242--1254.e6",
journal = "Cell Host and Microbe",
issn = "1931-3128",
publisher = "Cell Press",
number = "9",
}