Abstract
Porcine circovirus type 3 (PCV3) is an emerging swine pathogen associated with reproductive failure and systemic inflammation, but vaccines for related PCV2 provide limited cross-protection. Here, we determine high-resolution cryo-EM structures of PCV3 capsid protein assembled into virus-like particles (VLPs) and of PCV3 VLPs bound to the PCV3-specific antibody 2B5. The structures reveal differences from PCV2 in surface loops and define a conserved 2B5 epitope mainly involving the BC, EF and HI loops, providing a structural basis for PCV3-specific recognition. PCV3 VLPs induce sustained antibody responses in mice and pigs. In a pig challenge model, VLP immunization prevents viremia and viral replication in lungs and lymph nodes, as measured by quantitative PCR and in situ hybridization, with protection maintained for at least five months after boosting. These findings support PCV3 VLPs as a vaccine candidate against PCV3 infection.