Abstract
The MERS-CoV is an emerging virus, which already infected more than 1,300 humans with high (∼36%) mortality. Here, we show that m336, an exceptionally potent human anti-MERS-CoV antibody, is almost germline with only one somatic mutation in the heavy chain. The structure of Fab m336 in complex with the MERS-CoV receptor-binding domain reveals that its IGHV1-69-derived heavy chain provides more than 85% binding surface and that its epitope almost completely overlaps with the receptor-binding site. Analysis of antibodies from 69 healthy humans suggests an important role of the V(D)J recombination-generated junctional and allele-specific residues for achieving high affinity of binding at such low levels of somatic hypermutation. Our results also have important implications for development of vaccine immunogens based on the newly identified m336 epitope as well as for elucidation of mechanisms of neutralization by m336-like antibodies and their elicitation in vivo.Supplementary informationThe online version of this article (doi:10.1038/ncomms9223) contains supplementary material, which is available to authorized users.
Highlights
The MERS-CoV is an emerging virus, which already infected more than 1,300 humans with high (B36%) mortality
A 2.65-Å resolution data set in space group P212121 was collected at 22-ID beamline at the Advanced Photon Source with 20% glycerol as cryoprotectant, and structure solution by molecular replacement with the DDP4-bound MERS-CoV receptor-binding domain (RBD) and Fab revealed two Fab m336MERS-CoV RBD complexes occupying an asymmetric unit
By analysing the known RBD sequences, we found that the epitope of m336 does not overlap with any of the point mutations (Supplementary Fig. 6)
Summary
The MERS-CoV is an emerging virus, which already infected more than 1,300 humans with high (B36%) mortality. Our results have important implications for development of vaccine immunogens based on the newly identified m336 epitope as well as for elucidation of mechanisms of neutralization by m336-like antibodies and their elicitation in vivo. Neutralizing antibodies against some emerging viruses including severe acute respiratory syndrome coronavirus (SARS-CoV), Nipah and Hendra viruses, which cause acute infections, could be elicited within relatively short period of time after infection, and some of these antibodies were very close to their putative germline predecessors[8,9,10]. The structural characterization of the interactions between these germline-like antibodies and the viruses may represent a unique opportunity to understand the initial elicitation mechanism of the bnAbs and may eventually help the design of effective vaccine immunogens[4,7,11,12,13,14]. From any human coronavirus including SARS-CoV, but more related to the bat coronaviruses HKU4 and HKU5 (refs 17,18)
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