Wanwisa DejnirattisaiDaming ZhouHelen M. GinnHelen M.E. DuyvesteynPiyada SupasaJames Brett CaseYuguang ZhaoThomas S. WalterAlexander J. MentzerChang LiuBeibei WangGuido C. PaesenJose Slon-CamposCésar López-CamachoNatasha M. KafaiAdam L. BaileyRita E. ChenBaoling YingCraig ThompsonJai BoltonAlex FyfeSunetra GuptaTiong Kit TanJavier Gilbert-JaramilloWilliam JamesMichael KnightMiles W. CarrollDonal SkellyChristina DoldYanchun PengRobert LevinTao DongAndrew J. PollardJulian C. KnightPaul KlenermanNigel TempertonDavid R. HallMark A. WilliamsNeil G. PatersonFelicity K.R. BertramC. Alistair SiebertDaniel K. ClareAndrew HoweJulika RadeckeYun SongAlain R. TownsendKuan Ying A. HuangElizabeth E. FryJuthathip MongkolsapayaMichael S. DiamondJingshan RenDavid I. StuartGavin R. ScreatonNIHR Oxford Biomedical Research CentreOxford University Hospitals NHS Foundation TrustPublic Health EnglandDiamond Light SourceChang Gung University College of MedicineChang Gung Memorial HospitalWorthing HospitalUniversity of OxfordWashington University School of Medicine in St. LouisSir William Dunn School of PathologyFaculty of Medicine Siriraj Hospital, Mahidol UniversityUniversity of KentNuffield Department of MedicineUniversity of Oxford Medical Sciences DivisionInstruct-ERIC2022-08-042022-08-042021-04-15Cell. Vol.184, No.8 (2021), 2183-2200.e2210974172009286742-s2.0-85102643098https://repository.li.mahidol.ac.th/handle/123456789/76209Antibodies are crucial to immune protection against SARS-CoV-2, with some in emergency use as therapeutics. Here, we identify 377 human monoclonal antibodies (mAbs) recognizing the virus spike and focus mainly on 80 that bind the receptor binding domain (RBD). We devise a competition data-driven method to map RBD binding sites. We find that although antibody binding sites are widely dispersed, neutralizing antibody binding is focused, with nearly all highly inhibitory mAbs (IC50 < 0.1 μg/mL) blocking receptor interaction, except for one that binds a unique epitope in the N-terminal domain. Many of these neutralizing mAbs use public V-genes and are close to germline. We dissect the structural basis of recognition for this large panel of antibodies through X-ray crystallography and cryoelectron microscopy of 19 Fab-antigen structures. We find novel binding modes for some potently inhibitory antibodies and demonstrate that strongly neutralizing mAbs protect, prophylactically or therapeutically, in animal models.Mahidol UniversityBiochemistry, Genetics and Molecular BiologyArticleSCOPUS10.1016/j.cell.2021.02.032