mRNA delivery of a class 1/4 SARS-CoV-2 neutralizing antibody protects against diverse sarbecoviruses in a lethal mouse challenge model
Abstract
The unyielding antigenic drift of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), as well as the threat of future zoonotic sarbecovirus spillovers, has prompted the search for broadly neutralizing antibodies (bNAbs) to inform rational therapeutic and vaccine design. Here, we isolated and characterized 20 receptor binding domain (RBD)-directed bNAb lineages from a serially sampled SARS-CoV-2 patient who was infected and vaccinated during the early months of the pandemic. Thirteen of these targeted the highly conserved, cryptic class 1/4 or class 4 RBD epitopes and had long (18 to 26 amino acid) heavy chain complementarity determining region 3 loops that utilized the IGHD3-22 gene segment. Five bNAbs potently neutralized all 18 viruses in a panel containing SARS-CoV-2 variants up to the recently emerged XBB.1.5 and JN.1 strains as well as diverse sarbecoviruses from other clades. Structural analyses of the Ab401 and Ab568 bNAbs complexed with RBD and Spike trimer, respectively, revealed recognition features in common with other class 1/4 bNAbs. Prophylactic administration of Ab401 as a recombinant protein afforded robust protection against infectious challenge with either SARS-CoV-2_WA1 or a related bat sarbecovirus with zoonotic potential. A similar level of protection was achieved when the heavy and light chains of Ab401 were delivered as lipid nanoparticle-encapsulated mRNAs. These data expand the arsenal of SARS-CoV-2 bNAbs for clinical development and identify mRNA-based antibody delivery as a promising platform for both pandemic preparedness and protection of immunocompromised patients against emerging sarbecovirus variants.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (40)
Ashwin N. Skelly
Chengcheng Fan
Division of Biology and Biological Engineering, California Institute of Technology
Jennifer R. Keeffe
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.
Arya B. Ökten
Department of Laboratory Medicine, Yale School of Medicine
Edem Gavor
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.
Maddy L. Newby
School of Biological Sciences, University of Southampton, Southampton, UK.
Joel D. Allen
School of Biological Sciences, University of Southampton, Southampton, UK.
Edward F. Kreider
Wenge Ding
Rebecca A. Osbaldeston
Younghoon Park
Andrew J. Connell
Melinda G. Lituchy
Frederic Bibollet-Ruche
Katelyn M. Radford
Division of Biology and Biological Engineering, California Institute of Technology
Anthony P. West
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.
Mario A. Peña-Hernández
Department of Laboratory Medicine, Yale School of Medicine
Kendra Cruickshank
Departments of Medicine and Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Weimin Liu
Yingying Li
Amie Albertus
Brieyanna McWilliams
Department of Medicine, University of Pennsylvania
Ronnie M. Russell
Department of Medicine and Microbiology, Perelman School of Medicine, University of Pennsylvania
Kylie M. Konrath
Biomedical Graduate Studies, Perelman School of Medicine at the University of Pennsylvania
Jonathan L. Torres
Department of Integrative Structural and Computational Biology, The Scripps Research Institute
Meng Yuan
Hongmei Gao
Duke Human Vaccine Institute, Duke University Medical Center
David C. Montefiori
Duke Human Vaccine Institute, Duke University Medical Center
Michael S. Saag
Department of Medicine, University of Alabama at Birmingham
Paul A. Goepfert
Department of Medicine, University of Alabama at Birmingham
Daniel W. Kulp
Department of Biochemistry and Biophysics, The University of Pennsylvania
Andrew B. Ward
Ian A. Wilson
George M. Shaw
Raiees Andrabi
Max Crispin
School of Biological Sciences, University of Southampton, Southampton, UK.
Drew Weissman
Craig B. Wilen
Department of Laboratory Medicine, Yale School of Medicine
Pamela J. Bjorkman
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.
Beatrice H. Hahn