Revealing the molecular mechanism of MHC/peptide recognition by aP T-cell receptors (TCRs) (104) allowed the identification of a large number of immunogenic epitopes (105). Synthetic peptide combinatorial libraries proved to be a powerful tool for screening millions of peptide candidates, thus greatly speeding up discovery of new immunogenic epitopes (106), with immediate consequences for the design of vaccines. Numerous immunogenic epitopes have now been identified in many potential targets of vaccination ranging from important clinical pathogens, such as HIV, to antigens from a wide variety of tumors. Instead of using the entire coding region of an antigen in plasmid DNA, only a single epitope or several epitopes with known immunogenicity can be sequentially arranged into a single polypeptide, thus forming a string of epitopes. This so-called minigene or minimal-epitope approach takes advantage of the fact that plasmid DNA-encoded antigenic peptides can be loaded onto MHC class I molecules via the endogenous antigen-processing pathway. One of many examples of polyepitope vaccines that recently entered clinical trials is the polyepitope HIV-1 vaccine that is currently being evaluated in prime-boost regimens in Kenya (107). Several precautions have been taken into consideration while constructing this vaccine including: (a) fusion of coding sequence of 25 partially overlapping CTL epitopes to C-terminal coding sequence of truncated gag, (b) prevention of membrane localization of the recombinant protein, (c) inclusion of MHC class II-restricted epitopes, (d) inclusion of a 12-bp-long Kozak consensus sequence to optimize translation, (e) codon usage optimized for human genes, and (f) choice of multiallelic epitopes to cover a broad range of HLA alleles. The safety and efficiency of this vaccine was confirmed in several preclinical studies (108,109). It will take several years before the actual efficacy of this vaccine is known, but in the meantime, new improvements will certainly be introduced based on the growing knowledge of interactions between epitopes. For example, it was recently shown that certain HIV-1 epitopes have the potential to antagonize immunogenicity of others through the formation ofjunctional epitopes (110). Once such obstacles are eliminated, polyepitope DNA vaccines might prove superior to vaccines relying on the entire coding region of an antigen.
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