• Phillip Pymm, Amy Adair, Li-Jin Chan, James P Cooney, Francesca L Mordant, Cody C Allison, Ester Lopez, Ebene R Haycroft, Matthew T O'Neill, Li Lynn Tan, Melanie H Dietrich, Damien Drew, Marcel Doerflinger, Michael A Dengler, Nichollas E Scott, Adam K Wheatley, Nicholas A Gherardin, Hariprasad Venugopal, Deborah Cromer, Miles P Davenport, Raelene Pickering, Dale I Godfrey, Damian F J Purcell, Stephen J Kent, Amy W Chung, Kanta Subbarao, Marc Pellegrini, Alisa Glukhova, and Wai-Hong Tham.
• Infectious Diseases and Immune Defences Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
• Proc. Natl. Acad. Sci. U.S.A. 2021 May 11; 118 (19).

AbstractNeutralizing antibodies are important for immunity against SARS-CoV-2 and as therapeutics for the prevention and treatment of COVID-19. Here, we identified high-affinity nanobodies from alpacas immunized with coronavirus spike and receptor-binding domains (RBD) that disrupted RBD engagement with the human receptor angiotensin-converting enzyme 2 (ACE2) and potently neutralized SARS-CoV-2. Epitope mapping, X-ray crystallography, and cryo-electron microscopy revealed two distinct antigenic sites and showed two neutralizing nanobodies from different epitope classes bound simultaneously to the spike trimer. Nanobody-Fc fusions of the four most potent nanobodies blocked ACE2 engagement with RBD variants present in human populations and potently neutralized both wild-type SARS-CoV-2 and the N501Y D614G variant at concentrations as low as 0.1 nM. Prophylactic administration of either single nanobody-Fc or as mixtures reduced viral loads by up to 104-fold in mice infected with the N501Y D614G SARS-CoV-2 virus. These results suggest a role for nanobody-Fc fusions as prophylactic agents against SARS-CoV-2.Copyright © 2021 the Author(s). Published by PNAS.

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