Journal
JOURNAL OF INFECTIOUS DISEASES
Volume 218, Issue 8, Pages 1249-1260Publisher
OXFORD UNIV PRESS INC
DOI: 10.1093/infdis/jiy311
Keywords
crystallographic analysis; human monoclonal antibody; MERS-CoV; neutralizing antibody repertoires
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Funding
- National Key Research and Development Program of China [2016YFD0500300, 2016YFC1200901, 2016YFC1200200]
- Megaproject for Infectious Disease Research of China [2016ZX10004001-003]
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Background. The Middle East respiratory syndrome coronavirus (MERS-CoV) causes severe respiratory infection with a high (similar to 35%) mortality rate. Neutralizing antibodies targeting the spike of MERS-CoV have been shown to be a therapeutic option for treatment of lethal disease. Methods. We describe the germline diversity and neutralizing activity of 13 potent human monoclonal antibodies (mAbs) that target the MERS-CoV spike (S) protein. Biological functions were assessed by live MERS-CoV, pseudotype particle and its variants, and structural basis was also determined by crystallographic analysis. Results. Of the 13 mAbs displaying strong neutralizing activity against MERS-CoV, two with the immunoglobulin heavy-chain variable region (IGHV) 1-69-derived heavy chain (named MERS-GD27 and MERS-GD33) showed the most potent neutralizing activity against pseudotyped and live MERS-CoV in vitro. Mutagenesis analysis suggested that MERS-GD27 and MERS-GD33 recognized distinct regions in S glycoproteins, and the combination of 2 mAbs demonstrated a synergistic effect in neutralization against pseudotyped MERS-CoV. The structural basis of MERS-GD27 neutralization and recognition revealed that its epitope almost completely overlapped with the receptor-binding site. Conclusions. Our data provide new insights into the specific antibody repertoires and the molecular determinants of neutralization during natural MERS-CoV infection in humans. This finding supports additional efforts to design and develop novel therapies to combat MERS-CoV infections in humans.
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