Protective Immunity to Dengue Virus Induced by DNA Vaccines Encoding Nonstructural Proteins in a Lethal Challenge Immunocompetent Mouse Model

Dengue virus represents the main arbovirus affecting humans, but there are no effective drugs or available worldwide licensed vaccine formulations capable of conferring full protection against the infection. Experimental studies and results generated after the release of the anti-DENV vaccine demonstrated that induction of high-titer neutralizing antibodies does not represent a unique protection correlate and that, indeed, T cell-based immune responses plays a relevant role in the establishment of an immune protective state. In this context, this study aimed to further demonstrate protective features of immune responses elicited in C57BL/6 mice immunized with three plasmids encoding DENV2 nonstructural proteins (NS1, NS3, and NS5), which were subsequently challenged with a DENV2 strain naturally capable of inducing lethal encephalitis in immunocompetent mouse strains. The animals were immunized intramuscularly with two doses of the DNA vaccine mix at a 2-week interval. Cytokine profiles generated by spleen or brain-infiltrating mononuclear cells revealed increased IFN-γ levels in vaccinated animals. Survival curves after lethal challenge with DENV2 showed complete protection only among immunized mice. The results confirm the pivotal role of cellular immune responses targeting nonstructural DENV proteins and validate the experimental model based on a DENV2 strain capable of infecting and killing immunocompetent mice as a tool for the evaluation of protective immunity induced by anti-DENV vaccines.