DNA-based vaccine against La Crosse virus: Protective immune response mediated by neutralizing antibodies and CD4(+) T cells

La Crosse virus (LACV)-mediated encephalitis is the most frequently reporte d arboviral disease in the United States, but to date no vaccine against th is virus is available. We have established a new animal model, genetically targeted mice lacking a functional interferon type I receptor (IFNAR-1). Th ese mice show an age-independent susceptibility to LACV and develop an acut e encephalitis within 6 days of infection, thereby allowing the evaluation of vaccines against LACV. Taking advantage of this knockout mouse model, we have assessed the feasibility of DNA vaccination against this viral diseas e. Plasmid DNAs, encoding either the virus surface glycoproteins G1 and G2 or the internal nucleocapsid protein N, were used to immunize LFNAR-1-defic ient mice. Mice vaccinated with DNA encoding the glycoproteins G1 and G2 pr oduced neutralizing antibodies and exhibited a high degree of protection ag ainst challenge with high doses of LACV. Depletion of CD4(+) T cells in mic e vaccinated with DNA encoding G1/G2 reduced their capacity to control the infection. Virus titration and immunohistological analysis revealed that th e protected mice showed no evidence of LACV particles in the brain. This in dicates that the vaccine-induced immune response efficiently blocked viral spreading from the primary replication site to the brain. In contrast, immu nization with DNA encoding protein N yielded only a partial protective effe ct that can be attributed to the cellular immune response. Taken together, this study shows that DNA vaccines can be designed to efficiently induce a protective immune response based on neutralizing antibodies and CD4(+) T ce lls.