Bovine viral diarrhoea virus (BVDV) imposes significant economic burdens and biosecurity risks on the global animal trade and biological product industries. Addressing the challenges posed by the virus's complex subgenotypes requires the development of cross-protective vaccines. In this study, we evaluated the immunogenicity of two lipid nanoparticle-encapsulated mRNA (mRNA-LNP) vaccines: a full-length, membrane-anchored E2 (mE2) mRNA-LNP vaccine and a secretory, truncated E2 (tE2) mRNA-LNP vaccine, in both mice and calves. mE2 and tE2 mRNA-LNP induced robust E2-specific IgG antibodies and neutralising antibodies in mice. Neutralising antibody data further demonstrated that the mE2 mRNA-LNP exhibited superior immunogenicity compared with the tE2 mRNA-LNP in calves. Notably, administering two doses of the 100 μg mE2 mRNA-LNP effectively protected calves against BVDV challenge. Furthermore, the mE2 mRNA-LNP elicited robust cross-neutralising antibodies against multiple BVDV-1 and BVDV-2 strains for up to six months and induced promising cross-reactive cellular immune responses. The safety of mE2 mRNA-LNP was confirmed through the administration of two high doses (500 μg) in calves without adverse effects. Importantly, the rate of BVDV infection within the mE2 mRNA-LNP-vaccinated herd declined significantly, demonstrating that this vaccine effectively reduces BVDV transmission in field. In conclusion, this study comprehensively highlights the safety, efficacy, and broad cross-immune responses of the mE2 mRNA-LNP vaccine platform for preventing and controlling BVDV in calves.
