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Abstract: Coccidioides immitis is endemic in the soil of the desert Southwest. It causes a respiratory infection that is usually mild, but can last months and may disseminate beyond the lung. Disseminated infections can be fatal or require life-long therapy. Development of an effective vaccine may be a successful method of preventing serious disease. In this paper, we show that immunostimulatory-oligodeoxynucleotides (ISS-ODN) are an effective adjuvant for a recombinant coccidioidal protein known as antigen 2/proline rich antigen. Protective immunity induced by this ISS-ODN-based vaccine requires IL-12, interferon-γ and MHC Class II-restricted T-cells. Cytotoxic CD8 T-cells are not required. This study elucidates the mechanisms needed to elicit successful immunity against coccidioidomycosis, and holds promise for development of an effective coccidioidal vaccine against coccidioidomycosis. [Copyright &y& Elsevier]