Recombinant receptor-binding domains of multiple Middle East respiratory syndrome coronaviruses (MERS-CoVs) induce crossneutralizing antibodies against divergent human and camel MERS-CoVs and antibody escape mutants

Wanbo Tai, Yufei Wang, Craig A. Fett, Guangyu Zhao, Fang Li, Stanley Perlman, Shibo Jiang, Yusen Zhou, Lanying Du

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Abstract

Middle East respiratory syndrome coronavirus (MERS-CoV) binds to cellular receptor dipeptidyl peptidase 4 (DPP4) via the spike (S) protein receptor-binding domain (RBD). The RBD contains critical neutralizing epitopes and serves as an important vaccine target. Since RBD mutations occur in different MERS-CoV isolates and antibody escape mutants, cross-neutralization of divergent MERS-CoV strains by RBD-induced antibodies remains unknown. Here, we constructed four recombinant RBD (rRBD) proteins with single or multiple mutations detected in representative human MERS-CoV strains from the 2012, 2013, 2014, and 2015 outbreaks, respectively, and one rRBD protein with multiple changes derived from camel MERS-CoV strains. Like the RBD of prototype EMC2012 (EMC-RBD), all five RBDs maintained good antigenicity and functionality, the ability to bind RBD-specific neutralizing monoclonal antibodies (MAbs) and the DPP4 receptor, and high immunogenicity, able to elicit S-specific antibodies. They induced potent neutralizing antibodies cross-neutralizing 17 MERS pseudoviruses expressing S proteins of representative human and camel MERS-CoV strains identified during the 2012-2015 outbreaks, 5 MAb escape MERSCoV mutants, and 2 live human MERS-CoV strains. We then constructed two RBDs mutated in multiple key residues in the receptor-binding motif (RBM) of RBD and demonstrated their strong cross-reactivity with anti-EMC-RBD antibodies. These RBD mutants with diminished DPP4 binding also led to virus attenuation, suggesting that immunoevasion after RBD immunization is accompanied by loss of viral fitness. Therefore, this study demonstrates that MERS-CoV RBD is an important vaccine target able to induce highly potent and broad-spectrum neutralizing antibodies against infection by divergent circulating human and camel MERS-CoV strains.

Original languageEnglish (US)
Article numbere01651-16
JournalJournal of virology
Volume91
Issue number1
DOIs
StatePublished - 2017

Bibliographical note

Funding Information:
We thank Dimiter S. Dimitrov and Tianlei Ying at the National Institutes of Health for providing m336, m337, and m338 MAbs. This study was supported by NIH grants R01AI098775, U01AI124260, and R21AI109094 to S.J. and L.D., R01AI089728 and R01AI110700 to F.L., and PO1AI060699 to S.P. G.Z. and Y.Z. received funding from the China National Program of Infectious Disease (2014ZX10004001004). The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. We declare no conflict of interest.

Publisher Copyright:
© 2016 American Society for Microbiology.

Keywords

  • Antibody escape mutants
  • Cross-neutralization
  • MERS
  • MERS-CoV
  • Multiple strains
  • Receptor-binding domain
  • Spike protein

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