T cells are essential players in the defense against
infection. By targeting the MHC
class I antigen-presenting pathway with
peptide-based
vaccines,
antigen-specific T cells can be induced. However, low immunogenicity of
peptides poses a challenge. Here, we set out to increase immunogenicity of
influenza-specific CD8+
T cell epitopes. By substituting
amino acids in wild type sequences with non-proteogenic
amino acids, affinity for MHC can be increased, which may ultimately enhance cytotoxic CD8+ T cell responses. Since preventive
vaccines against viruses should induce a broad immune response, we used this method to optimize
influenza-specific
epitopes of varying dominance. For this purpose,
HLA-A*0201 epitopes GILGFVFTL, FMYSDFHFI and NMLSTVLGV were selected in order of decreasing MHC-affinity and dominance. For all
epitopes, we designed chemically enhanced altered
peptide ligands (CPLs) that exhibited greater binding affinity than their WT counterparts; even binding scores of the high affinity
GILGFVFTL epitope could be improved. When
HLA-A*0201 transgenic mice were vaccinated with selected CPLs, at least 2 out of 4 CPLs of each
epitope showed an increase in IFN-γ responses of splenocytes. Moreover, modification of the low affinity
epitope NMLSTVLGV led to an increase in the number of mice that responded. By optimizing three additional
influenza epitopes specific for
HLA-A*0301, we show that this strategy can be extended to other alleles. Thus, enhancing binding affinity of
peptides provides a valuable tool to improve the immunogenicity and range of preventive T cell-targeted
peptide vaccines.