A Self‐Amplifying RNA Lipid Nanoparticle (saRNA‐LNP) Vaccine Provides Effective Protection Against Porcine Epidemic Diarrhea

The development of vaccine platforms capable of inducing sustained, potent, and cost‐effective immunity remains a major challenge in veterinary vaccinology, particularly for coronaviruses, which are often associated with short‐lived vaccine‐induced protection. Here, we establish a self‐amplifying RNA (saRNA) lipid nanoparticle (LNP) vaccine platform and evaluate its application using porcine epidemic diarrhea virus (PEDV) as a representative coronavirus model. A single vaccination elicited robust specific humoral and cellular immune responses. Vaccinated piglets exhibited significantly higher specific IgG and neutralizing antibody titers of PEDV‐S (1:160) at 28 days postvaccination (dpv). Furthermore, elevated levels of serum IFN‐γ and IL‐4, along with enhanced CD4 + and CD8 + T cells, were observed. Vaccinated pregnant sows exhibited significantly higher PEDV neutralizing antibody titers (~1:224 or 256) in serum and colostrum samples. The saRNA‐LNP vaccine conferred both active immune protection against PED in immunized piglets and passive immunity in neonates via colostrum‐derived antibodies from vaccinated sows. Notably, the truncated spike protein antigen outperformed the full‐length spike protein in terms of immunogenicity, revealing the importance of careful testing in designing this PEDV saRNA vaccine. The saRNA‐LNP system represents a dose‐sparing, single‐dose vaccine platform with the potential to extend protective immunity, enhance maternal antibody responses, and reduce vaccination costs for PEDV and other veterinary coronaviruses.