TY - JOUR T1 - Landscape analysis of escape variants identifies SARS-CoV-2 spike mutations that attenuate monoclonal and serum antibody neutralization JF - bioRxiv DO - 10.1101/2020.11.06.372037 SP - 2020.11.06.372037 AU - Zhuoming Liu AU - Laura A. VanBlargan AU - Louis-Marie Bloyet AU - Paul W. Rothlauf AU - Rita E. Chen AU - Spencer Stumpf AU - Haiyan Zhao AU - John M. Errico AU - Elitza S. Theel AU - Mariel J. Liebeskind AU - Brynn Alford AU - William J. Buchser AU - Ali H. Ellebedy AU - Daved H. Fremont AU - Michael S. Diamond AU - Sean P. J. Whelan Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/01/11/2020.11.06.372037.abstract N2 - Although neutralizing antibodies against the SARS-CoV-2 spike (S) protein are a goal of COVID-19 vaccines and have received emergency use authorization as therapeutics, viral escape mutants could compromise their efficacy. To define the immune-selected mutational landscape in S protein, we used a VSV-eGFP-SARS-CoV-2-S chimeric virus and 19 neutralizing monoclonal antibodies (mAbs) against the receptor-binding domain (RBD) to generate 50 different escape mutants. The variants were mapped onto the RBD structure and evaluated for cross-resistance to mAbs and convalescent human sera. Each mAb had a unique resistance profile, although many shared residues within an epitope. Some variants (e.g., S477N) were resistant to neutralization by multiple mAbs, whereas others (e.g., E484K) escaped neutralization by convalescent sera, suggesting some humans induce a narrow repertoire of neutralizing antibodies. Comparing the antibody-mediated mutational landscape in S with sequence variation in circulating SARS-CoV-2, we define substitutions that may attenuate neutralizing immune responses in some humans.Competing Interest StatementM.S.D. is a consultant for Inbios, Vir Biotechnology, NGM Biopharmaceuticals, and on the Scientific Advisory Board of Moderna and Immunome. The Diamond laboratory has received unrelated funding support in sponsored research agreements from Moderna, Vir Biotechnology, and Emergent BioSolutions. The Ellebedy laboratory has received unrelated funding support in sponsored research agreements from Emergent BioSolutions and funding support in sponsored research agreement from AbbVie to further develop 2B04 and 2H04 as therapeutic mAbs. A.H.E. and Washington University have filed a patent application that includes the SARS-CoV-2 antibodies 2B04 and 2H04 for potential commercial development. S.P.J.W. and Z.H.L have filed a disclosure with Washington University for VSV-SARS-CoV-2 mutants to characterize antibody panels. S.P.J.W. and Washington University have filed a patent application on VSV-SARS-CoV-2. S.P.J.W has received unrelated funding support in sponsored research agreements with Vir Biotechnology, AbbVie and sAB therapeutics. ER -