Structural basis of receptor-binding adaptation of human-infecting H3N8 influenza A virus.

Summary

H3N8 hemagglutinin exhibits dual receptor binding, with G228S modestly increasing human receptor affinity and Q226L switching preference to human-type receptors. Cryo-EM structures reveal the molecular basis, and distinct antigenic sites vs H3N2 raise vaccine concerns, supporting enhanced surveillance of 226/228 variants.

Key Findings

• H3N8 HAs show dual receptor binding with avian preference; G228S slightly increases human receptor binding.
• Q226L mutation shifts receptor preference toward human-type receptors, while G228S enhances binding to both.
• Cryo-EM structures define the receptor-binding basis; antigenic sites differ from H3N2, raising vaccine efficacy concerns.
• Current human H3N8 isolates are not yet fully adapted for efficient human-to-human transmission.

Clinical Implications

Public health surveillance should prioritize HA positions 226/228 in H3N8; antigenic divergence suggests current H3N2-based immunity may not cross-protect, guiding vaccine strain considerations.

Limitations

• Findings rely on in vitro binding and structural models; in vivo human transmissibility remains inferential
• Antigenic analysis suggests divergence but does not test vaccine effectiveness directly

Future Directions

Longitudinal surveillance of HA 226/228 variants, functional fitness in mammalian models, and immunogenicity studies to inform candidate vaccines for H3N8.