SUMMARY Coccidioidomycosis, also known as Valley Fever (VF) impacts residents in arid regions of the world including southwestern US, areas in South and Central America and in Mexico. Annual incidences are rising overall with estimated increases in recent years of more than 200% in some areas. In addition, epidemiological studies indicate that the geographical range of VF is expanding and up to 17-29% of community-acquired pneumonia in these areas can be attributed to Coccidiodes infections. VF poses a significant and ongoing threat to human health, but to date, there is no safe and effective vaccine licensed for VF. As such, there is an urgent unmet need to develop a vaccine that can provide protection from the disease. Evidence suggests an effective vaccine for VF should be possible. Individuals who recover from VF will generally have lifelong immunity against re- exposure. Furthermore, early studies employing live attenuated vaccine strategies have demonstrated significant protection in mouse and nonhuman primate models of infection although due to the risk of severe reactogenicity and genetic reversion, a live attenuated vaccine for human use is not considered a viable approach. Nucleic acid vaccines, including both DNA and RNA vaccines, result in the intracellular expression of antigens, mimicking a live infection including induction of robust antibody and T cell responses, but without the risks associated with a live infection. Recent advances with both DNA and mRNA vaccine technologies have moved them to the forefront as one of the most effective vaccines strategies to induce protective immunity in humans, as evident by the current, highly efficacious licensed COVID-19 mRNA vaccines. In addition, DNA and RNA vaccines are rapid and simple, requiring only the genetic sequence of a given antigen to design. The ease and speed in constructing and producing DNA and RNA vaccines makes them an ideal tool to enable rapid screening of a large number of potential antigens to identify novel immunogens for a VF vaccine. Here, we propose to leverage advanced DNA and RNA vaccine delivery technologies developed at the University of Washington to identify novel immunogens for a VF vaccine and to investigate their immunogenicity and efficacy in animal models. Toward this goal, in collaboration with Research Projects 1 and 2 and the Animal Core, we propose to identify a lead nucleic acid vaccine platform for a VF vaccine (Aim 1), employ that technology to investigate candidate virulence factors and putative T cell epitopes as protective immunogens to design a lead vaccine composition that affords optimum immunogenicity, safety and efficacy in mice (Aim 2) and nonhuman primates (Aim 3). If successful, these studies could lead to development of a novel nucleic acid vaccine that can provide protection from Valley Fever.