Construction and Evaluation of a Novel Recombinant T Cell Epitope-Based Vaccine against Coccidioidomycosis
Open Access
- 1 November 2012
- journal article
- Published by American Society for Microbiology in Infection and Immunity
- Vol. 80 (11), 3960-3974
- https://doi.org/10.1128/iai.00566-12
Abstract
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.Keywords
This publication has 56 references indexed in Scilit:
- Polyfunctional responses by human T cells result from sequential release of cytokinesProceedings of the National Academy of Sciences of the United States of America, 2011
- Vaccine Immunity to Coccidioidomycosis Occurs by Early Activation of Three Signal Pathways of T Helper Cell Response (Th1, Th2, and Th17)Infection and Immunity, 2011
- MyD88 Signaling Is Required for Efficient Innate and Adaptive Immune Responses to Paracoccidioides brasiliensis InfectionInfection and Immunity, 2011
- Population genomic sequencing of Coccidioides fungi reveals recent hybridization and transposon controlGenome Research, 2010
- Interleukin‐17 and its target genes: mechanisms of interleukin‐17 function in diseaseImmunology, 2010
- Comparative genomic analyses of the human fungal pathogens Coccidioides and their relativesGenome Research, 2009
- A Genetically Engineered Live Attenuated Vaccine ofCoccidioides posadasiiProtects BALB/c Mice against CoccidioidomycosisInfection and Immunity, 2009
- Mapping short DNA sequencing reads and calling variants using mapping quality scoresGenome Research, 2008
- Multivalent Recombinant Protein Vaccine against CoccidioidomycosisInfection and Immunity, 2006
- Gapped BLAST and PSI-BLAST: a new generation of protein database search programsNucleic Acids Research, 1997