Construction and Evaluation of a Novel Recombinant T Cell Epitope-Based Vaccine against Coccidioidomycosis

Department of Biology and South Texas Center for Emerging Infectious Diseases, University of Texas at San Antonio, San Antonio, Texas, USA.
Infection and immunity (Impact Factor: 3.73). 09/2012; 80(11):3960-74. DOI: 10.1128/IAI.00566-12
Source: PubMed


Clinical and animal studies of coccidioidomycosis have demonstrated that activated CD4(+) T lymphocytes are essential for protection against this fungal respiratory disease. We previously reported a vaccine against Coccidioides infection which contained three recombinant CD4(+) T cell-reactive proteins and induced a robust, protective immune response in mice. Due to the anticipated high cost of production and clinical assessment of this multivalent vaccine, we generated a single protein which contained immunodominant T cell epitopes of the three polypeptides. Epitopes were initially identified by computational prediction of their ability to bind promiscuously to human major histocompatibility complex class II (MHC II) molecules. Cellular immunoassays confirmed the immunogenicity of the synthesized epitope peptides, while in vitro binding assays revealed a range of peptide affinity for MHC II. A DNA construct was synthesized for bacterial expression of a recombinant protein vaccine which contained five epitopes with the highest affinity for human MHC II, each fused with leader and spacer peptides proposed to optimize epitope processing and presentation to T cell receptors. Recall assays of immune T lymphocytes obtained from human MHC II-expressing HLA-DR4 transgenic mice confirmed that 4 of the 5 epitope peptides were processed. Mice immunized with the epitope-based vaccine admixed with a synthetic oligodeoxynucleotide adjuvant or loaded into yeast glucan particles and then challenged intranasally with Coccidioides showed early lung infiltration of activated T helper-1 (Th1), Th2, and Th17 cells, elevated gamma interferon (IFN-γ) and interleukin (IL)-17 production, significant reduction of fungal burden, and prolongation of survival compared to nonvaccinated mice. This is the first report of an epitope-based vaccine against coccidioidomycosis.

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Available from: Gary R Ostroff, Jul 16, 2014
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    • "β-glucan microparticles (GPs) represent an alternative antigen particle system for oral delivery. These hollow and porous GP are known for their safety, immunogenicity and high antigen encapsulation efficiency [10] [11] [12] [13] [14] [15] [16] [17] [18] [19]. These promising antigen carriers are derived from the cell wall of Saccharomyces cerevisiae (Baker's yeast) and are mainly composed of β-1,3- D-glucans, a 'microbe-associated molecular patterns' (MAMPs) with adjuvant ability [16] [20] [21]. "
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    • "It is possible that the conjugation of WGPs to proteins specific for Coccidioides could improve the effectiveness of the vaccine preparation. Similarly, the use of multivalent epitope constructs specific to Coccidioides delivered in shells of b-glucan have been shown to induce protective cell-mediated responses (Hurtgen et al., 2012; Cole et al., 2013). These data also support the concept of using glycans as carriers of fungal proteins, similar to our own results and those of Torosantucci et al. (2005), which take advantage of the immunostimulatory properties of b-glucan and reduce the need for an adjuvant such as aluminium hydroxide. "
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