A PEDV-spike-protein-expressing mRNA vaccine protects piglets against PEDV challenge. Researchers developed two lipid nanoparticle (LNP)-encapsulated mRNA vaccines encoding either the full-length PEDV spike (S) protein or a multiepitope chimeric spike (Sm) protein. The S mRNA-LNP vaccine showed superior immune responses in mice, inducing strong humoral and cellular immunity in piglets. It protected actively immunized piglets against PEDV and provided passive immunity through colostrum-derived antibodies after sow immunization. The vaccine demonstrated effective protection against PEDV infection in both actively and passively immunized piglets. The study highlights the potential of the PEDV-S mRNA vaccine as a promising candidate for combating PEDV. The vaccine's ability to induce both humoral and cellular immune responses, along with its effectiveness in protecting piglets, suggests its potential as a preventive vaccine. The study also shows that the S protein is a better target for mRNA vaccine development than the Sm version due to its potential for undiscovered neutralizing sites. The vaccine's broad-spectrum activity and flexibility make it a promising platform for future vaccine development. Passive immunity through colostrum is critical for protecting neonatal piglets against PEDV. The study demonstrates that the S mRNA vaccine can induce PEDV-specific IgG and IgA in sows, which are transferred to suckling piglets, providing effective passive immunity. Overall, the study shows that the PEDV-S mRNA vaccine is a promising candidate for preventing PEDV infection in piglets.A PEDV-spike-protein-expressing mRNA vaccine protects piglets against PEDV challenge. Researchers developed two lipid nanoparticle (LNP)-encapsulated mRNA vaccines encoding either the full-length PEDV spike (S) protein or a multiepitope chimeric spike (Sm) protein. The S mRNA-LNP vaccine showed superior immune responses in mice, inducing strong humoral and cellular immunity in piglets. It protected actively immunized piglets against PEDV and provided passive immunity through colostrum-derived antibodies after sow immunization. The vaccine demonstrated effective protection against PEDV infection in both actively and passively immunized piglets. The study highlights the potential of the PEDV-S mRNA vaccine as a promising candidate for combating PEDV. The vaccine's ability to induce both humoral and cellular immune responses, along with its effectiveness in protecting piglets, suggests its potential as a preventive vaccine. The study also shows that the S protein is a better target for mRNA vaccine development than the Sm version due to its potential for undiscovered neutralizing sites. The vaccine's broad-spectrum activity and flexibility make it a promising platform for future vaccine development. Passive immunity through colostrum is critical for protecting neonatal piglets against PEDV. The study demonstrates that the S mRNA vaccine can induce PEDV-specific IgG and IgA in sows, which are transferred to suckling piglets, providing effective passive immunity. Overall, the study shows that the PEDV-S mRNA vaccine is a promising candidate for preventing PEDV infection in piglets.