Graduate Research Assistant Univ. of Texas, San Antonio, Texas, United States
Disclosure(s):
Reimi Navarro, M.S.: No financial relationships to disclose
Introduction/Rationale: Valley Fever (VF) is a potentially fatal fungal disease caused by Coccidioides; however, no clinical vaccine exists. We previously created a recombinant Coccidioides antigen, rCpa1, with DRB1*04:01 (DR4) epitopes, but it is poorly expressed in E. coli. To enhance solubility and broaden HLA coverage, we removed 25 amino acids and incorporated three new DRB1*03:01 (DR3) epitopes, generating the rCpa5 antigen. We formulated rCpa5 with glucan-chitin particles (GCPs) as an adjuvant/delivery system. We hypothesize that GCP-rCpa5 can protect against VF by activating Th1/Th17 responses.
Methods: C57BL/6 (BL/6), DR4, and DR3 transgenic mice were vaccinated subcutaneously three times with GCP-rCpa5, and T cell epitopes were mapped by IFN-γ recall assays. Vaccinated and control mice were challenged intranasally to determine efficacy by survival (45 DPC) and fungal burden at 7 and 14 DPC. Lung T cell responses were profiled by intracellular cytokine assays. Additionally intramuscular and oropharyngeal vaccination routes were compared to identify the optimal route.
Results: The yield of the rCpa5 antigen was improved over 100-fold compared to rCpa1. We identified 14, 12, and 9 novel T cell epitopes within rCpa5 for BL/6, DR4, and DR3 mice, respectively. GCP-rCpa5 vaccination conferred 90% survival for BL/6 mice versus 10% in controls. Vaccinated DR4 mice showed a significant reduction in fungal burden in the lungs and spleen, with elevated Th1/Th17 responses compared to control mice. Comparable fungal clearance was observed across all three vaccination routes.
Conclusion: The rCpa5 antigen contains multiple epitopes for prevalent human MHC-II alleles and the GCP-rCpa5 vaccine is effective against Coccidioides infection for laboratory and humanized mice. Vaccine-induced protection is associated with mixed Th1/Th17 responses elicited by subcutaneous, oropharyngeal, and intramuscular vaccination. These data support that GCP-rCpa5 is protective and worthy of further development for clinical application.
