Nervous necrosis virus (NNV), which causes viral encephalopathy and retinopathy, is one of the most devastating viruses of cultured marine fishes worldwide, with mortality rates up to 100% in larvae and juveniles.In this study, the OGNNV coat protein(CP) gene was optimized by MaxCodon TM Optimization Program(V13) and subcloned into pET30a.Soluble OGNNV-CP was efficiently produced in BL21(DE3), and could self-assemble into VLPs.Their ability to invade sensitive cells was identified.OGNNV-VLPs were used as vaccine to immunize orange-spotted grouper larvae with three different approaches.Finally, the antibody responses after vaccination were detected, and the expression profiles of NNV gene and survival rate after virus attacks were investigated.