Effects of Human Anti-Spike Protein Receptor Binding Domain Antibodies on Severe Acute Respiratory Syndrome Coronavirus Neutralization Escape and Fitness

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  • Jianhua Sui
    • Other Affiliation: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute; Department of Medicine, Harvard Medical School, Boston Massachusetts, USA
  • Meagan Deming
    • Other Affiliation: Departments of Epidemiology and Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina, USA
  • Barry Rockx
    • Other Affiliation: Departments of Epidemiology and Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina, USA
  • Robert C. Liddington
    • Other Affiliation: Infectious and Inflammatory Disease Center, Stanford-Burnham Medical Research Institute, La Jolla, California, USA
  • Quan Karen Zhu
    • Other Affiliation: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute; Department of Medicine, Harvard Medical School, Boston Massachusetts, USA
  • Ralph S. Baric
    • Other Affiliation: Departments of Epidemiology and Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina, USA
  • Wayne A. Marascoa
    • Other Affiliation: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute; Department of Medicine, Harvard Medical School, Boston Massachusetts, USA
Abstract
  • The receptor binding domain (RBD) of the spike (S) glycoprotein of severe acute respiratory syndrome coronavirus (SARS-CoV) is a major target of protective immunity in vivo. Although a large number of neutralizing antibodies (nAbs) have been developed, it remains unclear if a single RBD-targeting nAb or two in combination can prevent neutralization escape and, if not, attenuate viral virulence in vivo. In this study, we used a large panel of human nAbs against an epitope that overlaps the interface between the RBD and its receptor, angiotensin-converting enzyme 2 (ACE2), to assess their cross-neutralization activities against a panel of human and zoonotic SARS-CoVs and neutralization escape mutants. We also investigated the neutralization escape profiles of these nAbs and evaluated their effects on receptor binding and virus fitness in vitro and in mice. We found that some nAbs had great potency and breadth in neutralizing multiple viral strains, including neutralization escape viruses derived from other nAbs; however, no single nAb or combination of two blocked neutralization escape. Interestingly, in mice the neutralization escape mutant viruses showed either attenuation (Urbani background) or increased virulence (GD03 background) consistent with the different binding affinities between their RBDs and the mouse ACE2. We conclude that using either single nAbs or dual nAb combinations to target a SARS-CoV RBD epitope that shows plasticity may have limitations for preventing neutralization escape during in vivo immunotherapy. However, RBD-directed nAbs may be useful for providing broad neutralization and prevention of escape variants when combined with other nAbs that target a second conserved epitope with less plasticity and more structural constraint.
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  • Article
Rights statement
  • In Copyright
Journal title
  • Journal of Virology
Journal volume
  • 88
Journal issue
  • 23
Page start
  • 13769
Page end
  • 13780
Language
  • English
ISSN
  • 1070-6321
  • 1098-5514
  • 0022-538X
Publisher
  • American Society for Microbiology

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