Strategies to enhance immunogenicity of cDNA vaccine encoded antigens by modulation of antigen processing |
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Institution: | 1. Laboratory of Molecular Genetics of Intracellular Transport, Institute of Gene Biology, Russian Academy of Sciences, 34/5, Vavilov St., 199334 Moscow, Russia;2. Department of Biophysics, Faculty of Biology, Moscow State University, 1–12, Leninskie Gory, 119991 Moscow, Russia |
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Abstract: | Most vaccines are based on protective humoral responses while for intracellular pathogens CD8+ T cells are regularly needed to provide protection. However, poor processing efficiency of antigens is often a limiting factor in CD8+ T cell priming, hampering vaccine efficacy. The multistage cDNA vaccine H56, encoding three secreted Mycobacterium tuberculosis antigens, was used to test a complete strategy to enhance vaccine’ immunogenicity. Potential CD8+ T cell epitopes in H56 were predicted using the NetMHC3.4/ANN program. Mice were immunized with H56 cDNA using dermal DNA tattoo immunization and epitope candidates were tested for recognition by responding CD8+ T cells in ex vivo assays. Seven novel CD8+ T cell epitopes were identified. H56 immunogenicity could be substantially enhanced by two strategies: (i) fusion of the H56 sequence to cDNA of proteins that modify intracellular antigen processing or provide CD4+ T cell help, (ii) by substitution of the epitope’s hydrophobic C-terminal flanking residues for polar glutamic acid, which facilitated their proteasome-mediated generation. We conclude that this whole strategy of in silico prediction of potential CD8+ T cell epitopes in novel antigens, followed by fusion to sequences with immunogenicity-enhancing properties or modification of epitope flanking sequences to improve proteasome-mediated processing, may be exploited to design novel vaccines against emerging or ‘hard to treat’ intracellular pathogens. |
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