An multivalent vaccine elicits protective Th17 response via activation of C-type lectin receptor- and Card9-mediated signal against pulmonary Coccidioides posadasii infection

Abstract

Abstract Coccidioidomycosis is a potentially life-threatening fungal infection that is responsible for ~150,000 infections annually in the United States. Development of a vaccine against Coccidioides infection is urgent. We have created a multivalent coccidioidal antigen (rCpa1) that contains promiscuous human T cell epitopes. The rCpa1 was formulated with 5 types of experimental adjuvants including yeast cell-wall particles and CpG adjuvant. The rCpa1 formulated with glucan chitin particles (GCPs) derived from a non-pathogenic yeast demonstrated the best protective efficacy for susceptible C57BL/6 and HLA-DR4 transgenic mice against this disease compared to the other 4 tested vaccines. This is the first report of a subunit vaccine that can provide a comparable degree of protection to a live, attenuated vaccine against coccidioidomycosis. The GCP-rCpa1 vaccine elicited a robust and durable Th17 memory response. Depletion of Th17 cells significantly reduced the protective efficacy of this vaccine, indicating that Th17 cells play an indispensable role. Dectin-1 and Dectin-2 molecules can bind to the GCP-rCpa1 vaccine particles. Macrophages derived from mice lacking expression of Dectin-1, Dectin-2 and downstream immune adapter CARD9 secreted reduced amounts of IL-1β and IL-6 upon stimulation with GCP-rCpa1 that are essential for Th17 development. Furthermore, vaccinated Dectin-1−/−, Dectin-2−/− and CARD9 −/− mice recruited significantly reduced amounts of Th17 cells to the lungs compared to C57BL/6 mice and succumbed to coccidioidomycosis. Taken together, protection against Coccidioides provided by GCP-rCpa1 vaccine requires Dectin-1- and Dectin-2-CARD9-mediated signaling to activate Th17 immune response.