Abstract Coccidioidomycosis (Valley Fever) is a systemic infection caused by the fungi Coccidioides immitis orCoccidioides posadasii which are endemic to Arizona California and other parts of the United States. Illnessranges from pneumonia to life-threatening spread to other parts of the body (disseminated infection)including the brain. Valley Fever causes an average of 160 deaths annually and produced $2 billion inhospital charges from 2000 2011. Current therapies are not curative and may be need to be continued forlife. This proposal responds to RFA-AI-16-034 which explicitly invites vaccines for Coccidioides spp. Our vaccine candidate appears i) safe ii) highly effective and iii) feasible to produce commercially. It isbased upon a deletion of the CPS1 gene from the fungus resulting in complete loss of virulence in mice.When used as a vaccine against experimental murine coccidioidomycosis it is very protective. The vaccinecandidate (cps1) is manufactured by simply growing arthroconidia on solid media and so the cost of goodsis likely to be low making commercial development feasible. We propose to develop our vaccine candidatefirst to prevent Valley Fever in dogs. This will provide pre-clinical information for its safety and efficacy in alarge animal and further support an FDA IND for humans. The specific aims are to first use fungal geneticanalysis of the CPS1 mutation to determine why it is essential for virulence. A complete understanding of itsrole in the fungus could provide a better assessment about its safety as a live vaccine. Second we willdevelop a formulation that would be used in both dogs and humans. Third we will determine exactly whichlymphocyte subsets and their cytokines mediate protection. This information will be useful for the rationalidentification of future surrogate markers of protection in immunized dogs and humans. Finally we will developan experimental model of coccidioidal infection in canines and use it to test the efficacy of cps1 to preventdisease. In addition to the studies proposed in this application we have identified an industrial partner AniviveLifesciences that has agreed to partner with us and will provide additional investment and expertise to fullydevelop a veterinary vaccine. We believe that with the success of this program risk of developing our vaccinecandidate for humans will be substantially reduced to the point that further investment will be forthcoming tocomplete the ultimate objective of our work.