Since DNA’s ability to generate an immune response was first described over 25 years ago, much work has been done to realize DNA’s full potential as a safe and potent vaccine candidate. Renewed research has focused on continually improving the potency of the platform, which has led to advancements in electroporation, DNA formulation, and novel synthesized sequence optimizations, allowing newer “synthetic” DNA vaccines (SDNA) to contend as a major vaccine platform. Further insights into factors that influence SDNA vaccine outcomes are critical to achieving full potential. Here, we designed novel SDNA encoded skin-derived cytokines within the IL-36 family, to assess their impact on immunity against several viral targets. Zika virus challenge studies were also performed to assess whether observed adjuvant activity led to improved challenge outcome. The studies show that codelivery of optimized IL-36 gamma, with a non-protective dose of a Zika SDNA vaccine, can enhance immune responses, allowing for protection against challenge compared to nonadjuvanted mice. Another important area that is relatively understudied is skin delivery of SDNA vaccines. The skin is a major immune organ, and expanded applications for immunization might be possible with better understanding of its potential in the context of newer SDNA technology. To test the impact of skin vaccination on a relevant pathogen challenge, two consensus SDNA vaccines that encode a Leishmania antigen, PEPCK, were designed incorporating several genetic improvements including RNA and codon optimization and addition of a highly efficient IgE leader sequence. These were used to immunize mice intramuscularly or intradermally and analyze the resulting immunity. We observed that intradermal vaccination drove a greater number of antigen specific skin resident T cells in the skin compared to intramuscular vaccination, both at the vaccination and distal site. We further observed that mice immunized intradermally were better protected against parasite challenge and burden compared to intramuscularly immunized mice. My thesis supports the idea that the skin represents both a robust source of important immune modulators that can improve vaccination outcome and a unique site for SDNA immunization that gives rise to long lived resident immune cells which may play a crucial role in generating effective interventions against infectious agents and cancer.