TY - JOUR T1 - Identification of broad, potent antibodies to functionally constrained regions of SARS-CoV-2 spike following a breakthrough infection JF - bioRxiv DO - 10.1101/2022.12.15.520606 SP - 2022.12.15.520606 AU - Jamie Guenthoer AU - Michelle Lilly AU - Tyler N. Starr AU - Bernadeta Dadonaite AU - Klaus N. Lovendahl AU - Jacob T. Croft AU - Caitlin I. Stoddard AU - Vrasha Chohan AU - Shilei Ding AU - Felicitas Ruiz AU - Mackenzie S. Kopp AU - Andrés Finzi AU - Jesse D. Bloom AU - Helen Y. Chu AU - Kelly K. Lee AU - Julie Overbaugh Y1 - 2022/01/01 UR - http://biorxiv.org/content/early/2022/12/16/2022.12.15.520606.abstract N2 - The antiviral benefit of antibodies can be compromised by viral escape especially for rapidly evolving viruses. Therefore, durable, effective antibodies must be both broad and potent to counter newly emerging, diverse strains. Discovery of such antibodies is critically important for SARS-CoV-2 as the global emergence of new variants of concern (VOC) has compromised the efficacy of therapeutic antibodies and vaccines. We describe a collection of broad and potent neutralizing monoclonal antibodies (mAbs) isolated from an individual who experienced a breakthrough infection with the Delta VOC. Four mAbs potently neutralize the Wuhan-Hu-1 vaccine strain, the Delta VOC, and also retain potency against the Omicron VOCs, including recently circulating BA.4/BA.5, in both pseudovirus-based and live virus assays, and one also potently neutralizes SARS-CoV-1. The potency of these mAbs was greater against Omicron VOCs than all but one of the mAbs that had been approved for therapeutic applications. The mAbs target distinct epitopes on the spike glycoprotein, three in the receptor binding domain (RBD) and one in an invariant region downstream of the RBD in subdomain 1 (SD1). The escape pathways we defined at single amino acid resolution with deep mutational scanning show they target conserved, functionally constrained regions of the glycoprotein, suggesting escape could incur a fitness cost. Overall, these mAbs are novel in their breadth across VOCs, their epitope specificity, and include a highly potent mAb targeting a rare epitope outside of the RBD in SD1.Competing Interest StatementT.N.S. consults for Apriori Bio on deep mutational scanning. J.D.B. serves as a scientific advisor to Apriori Bio and Oncorus. Subsequent to the completion of the research described in this manuscript, he also began to serve as a scientific advisor to Aerium Therapeutics and the Vaccine Company. H.Y.C reported consulting with Ellume, Merck, Abbvie, Pfizer, Medscape, Vindico, and the Bill and Melinda Gates Foundation. She has received research funding from Gates Ventures, and support and reagents from Ellume and Cepheid outside of the submitted work. J.O. is a consultant for Aerium Therapeutics. ER -