Since it was first reported in 1987, porcine reproductive and respiratory syndrome virus (PRRSV) has caused numerous economic losses worldwide. The extensive spread of PRRSV NADC30-like strains associated with clinical outbreaks in China represents a significant epidemiological concern. The lack of safe and effective vaccines that specifically target NADC30-like strains remains a critical gap in current PRRS control strategies. In this study, we firstly constructed four multi-antigen mRNA vaccine candidates, encoding recombinant fusion proteins that express distinct combinations of four envelope glycoproteins (GP2a, GP3, GP4, and GP5) derived from NADC30-like PRRSV, designated as GP35m-LNP, GP45m-LNP, GP345m-LNP, and GP2345m-LNP. The four mRNA-LNPs all demonstrated abundant proteins expression in vitro. And GP45m-, GP345m- and GP2345m-LNPs showed efficient antigen secretion properties. Mice experiment results showed that GP345m-LNP elicited the antigen-specific IgG titer and increased frequencies of IL-2-, IL-4- and IFN-γ-producing CD4T cells, as well as IFN-γ-producing CD8T cells. Immunization of piglets with GP345m-LNP effectively triggered specific cellular immune responses, significantly increasing PRRSV-specific IFN-γ production compared to the commercial inactivated vaccine and PBS-LNP groups. Following challenge, GP345m-LNP vaccination reduced the PRRSV viremia, pulmonary viral loads, and attenuated lung damage effectively. It indicated that the GP345m-LNP could provide protective efficacy against NADC30-like PRRSV challenge, serving as a prospective vaccine candidate for PRRSV control. + +
