Abstact

Enterovirus D68 (EV-D68) primarily causes respiratory illnesses and has been implicated in acute flaccid myelitis. Although virus-like particle (VLP) and traditional inactivated whole-virion (IWV) vaccines have demonstrated efficacy in mice, their immunological differences remain undetermined. Here, we directly compared the immunogenic and structural properties of VLP and IWV vaccines derived from the same EV-D68 strain under identical conditions. Although VLP induced significantly lower levels of EV-D68-specific IgG than IWV, neutralizing antibody titers and protective effects against viral challenge were comparable between the two groups in mice. Passive transfer experiments in neonatal mice further confirmed protection against lethal infection for both vaccine groups. Notably, in contrast to the IWV vaccine, the VLP vaccine elicited antibodies that preferentially recognized a limited subset of epitopes. Cryo-electron microscopy analyses revealed that VLPs structurally resemble the native virus but display distinct features in regions corresponding to epitopes that show differential antibody reactivity between VLP and IWV vaccines. By integrating structural and immunological analyses, we established a mechanistic framework linking capsid architecture to vaccine-induced antibody specificity. These findings suggest that VLP is a promising EV-D68 vaccine antigen with distinct epitope recognition profiles driven by structural characteristics.