Identification of human neutralizing antibodies against MERS-CoV and their role in virus adaptive evolution

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  • Tang, Xian-Chun
    • Other Affiliation: Harvard Medical School
  • Agnihothram, Sudhakar
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
  • Jiao, Yongjun
    • Other Affiliation: Harvard Medical School
  • Stanhope, Jeremy
    • Other Affiliation: Harvard Medical School
  • Graham, Rachel L.
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
  • Peterson, Eric C.
    • Other Affiliation: Harvard Medical School
  • Avnir, Yuval
    • Other Affiliation: Harvard Medical School
  • Tallarico, Amy St. Clair
    • Other Affiliation: Harvard Medical School
  • Sheehan, Jared
    • Other Affiliation: Harvard Medical School
  • Zhu, Quan
    • Other Affiliation: Harvard Medical School
  • Baric, Ralph S.
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
  • Marasco, Wayne A.
    • Other Affiliation: Harvard Medical School
Abstract
  • The newly emerging Middle East Respiratory Syndrome coronavirus (MERS-CoV) causes a Severe Acute Respiratory Syndrome-like disease with ∼43% mortality. Given the recent detection of virus in dromedary camels, zoonotic transfer of MERS-CoV to humans is suspected. In addition, little is known about the role of human neutralizing Ab (nAb) pressure as a driving force in MERS-CoV adaptive evolution. Here, we used a well-characterized nonimmune human Ab-phage library and a panning strategy with proteoliposomes and cells to identify seven human nAbs against the receptor-binding domain (RBD) of the MERS-CoV Spike protein. These nAbs bind to three different epitopes in the RBD and human dipeptidyl peptidase 4 (hDPP4) interface with subnanomolar/nanomolar binding affinities and block the binding of MERS-CoV Spike protein with its hDPP4 receptor. Escape mutant assays identified five amino acid residues that are critical for neutralization escape. Despite the close proximity of the three epitopes on the RBD interface, escape from one epitope did not have a major impact on neutralization with Abs directed to a different epitope. Importantly, the majority of escape mutations had negative impacts on hDPP4 receptor binding and viral fitness. To our knowledge, these results provide the first report on human nAbs against MERS-CoV that may contribute to MERS-CoV clearance and evolution. Moreover, in the absence of a licensed vaccine or antiviral for MERS, this panel of nAbs offers the possibility of developing human mAb-based immunotherapy, especially for health-care workers.
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  • Article
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  • In Copyright
Journal title
  • Proceedings of the National Academy of Sciences of the United States of America
Journal volume
  • 111
Journal issue
  • 19
Page start
  • e2018
Page end
  • e2026
Language
  • English

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