Neutralizing antibodies elicited in nonhuman primates by an enterovirus D68 virus-like particle vaccine target receptor binding sites.

Summary

VLP immunization in nonhuman primates elicited monoclonal antibodies that map to EV-D68’s receptor-binding interfaces, bridging sialic acid and MFS6 sites. These mAbs neutralize by disrupting multiple lifecycle steps, including promoting premature uncoating, and conferred in vivo protection comparable to a benchmark human mAb, while revealing single-residue escape routes.

Key Findings

• Five potently neutralizing NHP-derived mAbs targeted overlapping epitopes near the VP1 fivefold axis.
• Cryo-EM localized mAb epitopes bridging the sialic acid and MFS6 receptor-binding sites on the capsid.
• mAbs neutralized by disrupting multiple lifecycle steps, including promoting premature uncoating.
• VLP-elicited antibodies protected in a mouse challenge model comparably to a best-in-class human mAb.
• Single amino acid substitutions in capsid conferred viral escape, highlighting antigenic drift risks.

Clinical Implications

Structure-guided VLP vaccines targeting conserved receptor-binding epitopes may yield broader and more escape-resistant protection; surveillance for escape mutations should accompany clinical development.

Limitations

• Escape with single-residue capsid mutations raises concerns about antigenic drift.
• Protection and breadth were evaluated in animal models; human immunogenicity and durability remain to be established.

Future Directions

Design mosaic or multivalent VLPs focusing on conserved receptor-binding surfaces; test antibody cocktails to mitigate escape; advance to phase 1 trials with integrated genomic surveillance for drift.