Abstract
Enterovirus 71 (EV71)-neutralizing antibodies correlate with protection and have potential as therapeutic agents. We isolate and characterize a panel of plasmablast-derived monoclonal antibodies from an infected child whose antibody response focuses on the plateau epitope near the icosahedral 3-fold axes. Eight of a total of 19 antibodies target this epitope and three of these potently neutralize the virus. Representative neutralizing antibodies 38-1-10A and 38-3-11A both confer effective protection against lethal EV71 challenge in hSCARB2-transgenic mice. The cryo-electron microscopy structures of the EV71 virion in complex with Fab fragments of these potent and protective antibodies reveal the details of a conserved epitope formed by residues in the BC and HI loops of VP2 and the BC and HI loops of VP3 spanning the region around the 3-fold axis. Remarkably, the two antibodies interact with the epitope in quite distinct ways. These plateau-binding antibodies provide templates for promising candidate therapeutics.
Highlights
Enterovirus 71 (EV71)-neutralizing antibodies correlate with protection and have potential as therapeutic agents
The canyon had been assumed to interact with another receptor, scavenger receptor class B member 2 (SCARB2)[11], but a recent structural study revealed that SCARB2 binds to EV71 on the southern rim of the canyon, rather than across the canyon[12]
The cryo-electron microscopy structures of the EV71 virion in complex with two representative plateau-binding neutralizing antibodies reveal that their binding footprints are conserved in the great majority of circulating EV71 strains and these antibodies are therapeutic for lethal challenge in a murine infection
Summary
Enterovirus 71 (EV71)-neutralizing antibodies correlate with protection and have potential as therapeutic agents. In contrast to the canyon and fivefold vertex epitopes, the margin of the pentamer is not within or adjacent to known receptor binding sites, but we have shown that natural infection can induce neutralizing antibody responses to this part of the viral capsid (notably the so-called the plateau epitope, located close to the icosahedral threefold axes)[13]. The structural basis of how this epitope is important for cellular interactions and virus neutralization, which might guide the development of effective vaccines and immunotherapeutics against EV71, is lacking These issues emphasize the need for a deeper understanding of the human immune response to EV71 viruses. The cryo-electron microscopy (cryo-EM) structures of the EV71 virion in complex with two representative plateau-binding neutralizing antibodies reveal that their binding footprints are conserved in the great majority of circulating EV71 strains and these antibodies are therapeutic for lethal challenge in a murine infection. A subset of protective and potent plateau-binding antibodies possesses variable domain sequences 99.5–100% identical to germlines, suggesting that the fast and effective elicitation of such antibodies by immunization is feasible
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