Fenwick, CraigTurelli, PriscillaPerez, LaurentPellaton, CelineEsteves-Leuenberger, LineFarina, AlexCampos, JeremyLana, EricaFiscalini, FlurinRaclot, CharlenePojer, FlorenceLau, KelvinDemurtas, DavideDescatoire, MarcJoo, Victor S.Foglierini, MathildeNoto, AlessandraAbdelnabi, RanaFoo, Caroline S.Vangeel, LauraNeyts, JohanDu, WenjuanBosch, Berend-JanVeldman, GeertruidaLeyssen, PieterThiel, VolkerLeGrand, RogerLevy, YvesTrono, DidierPantaleo, Giuseppe2021-11-062021-11-062021-11-062021-10-1210.1016/j.celrep.2021.109814https://infoscience.epfl.ch/handle/20.500.14299/182917WOS:000707017600013Control of the ongoing SARS-CoV-2 pandemic is endangered by the emergence of viral variants with increased transmission efficiency, resistance to marketed therapeutic antibodies, and reduced sensitivity to vaccine-induced immunity. Here, we screen B cells from COVID-19 donors and identify P5C3, a highly potent and broadly neutralizing monoclonal antibody with picomolar neutralizing activity against all SARS-CoV-2 variants of concern (VOCs) identified to date. Structural characterization of P5C3 Fab in complex with the spike demonstrates a neutralizing activity defined by a large buried surface area, highly overlapping with the receptor-binding domain (RBD) surface necessary for ACE2 interaction. We further demonstrate that P5C3 shows complete prophylactic protection in the SARS-CoV-2-infected hamster challenge model. These results indicate that P5C3 opens exciting perspectives either as a prophylactic agent in immunocompromised individuals with poor response to vaccination or as combination therapy in SARS-CoV-2-infected individuals.Cell Biologyhuman monoclonal-antibodiescryo-em structurereceptor-bindingvisualizationvalidationspiketext::journal::journal article::research article