title: Characterization of a reduced peptide bond analogue of a promiscuous CD4 T cell epitope derived from the Plasmodium falciparum malaria vaccine candidate merozoite surface protein 1.
abstract: Use of synthetic peptides as vaccine components is hampered by their susceptibility to enzymatic degradation and rapid clearance from biological fluids. Introduction of non-natural structural modifications can render peptides more resistant to enzymatic degradation, encouraging attempts to profile such non-natural ligands as components of synthetic sub-unit vaccines. We have compared the antigenic and immunogenic properties of a series of non-natural peptide analogues derived from a promiscuous T cell epitope of the major Plasmodium falciparum malaria vaccine candidate merozoite surface protein 1 (MSP-1). A series of HLA class II restricted MSP-1(38-58)-specific TCC established from three volunteers were characterized for their minimal epitope and fine specificity. T cell stimulatory activities of a series of pseudo-peptide analogues with single reduced peptide bond Psi-[CH2-NH] modifications were compared with those of single d-amino acid replacement analogues. Compared to reduced peptide bond analogues the single d-amino acid replacement analogues turned out to be less suitable for stimulation of TCC. In particular, the reduced peptide analogue carrying a Psi-[CH2-NH] backbone modification between positions V52 and L53 of MSP-1(38-58) demonstrated properties that would make it a more suitable vaccine component than the unmodified parent peptide. First, the pseudo-peptide stimulated a number of TCC restricted by a range of HLA class II alleles. Second, trypsin treatment in combination with T cell stimulation assays provided evidence for increased resistance to proteolytic digestion. Third, the parasite-binding anti-MSP-1 mAb 7.27 recognized best this particular pseudo-peptide in competition ELISA experiments and its immunogenicity in out-bred Aotus monkeys was superior to that of the parent peptide eliciting antibodies cross-reactive with native MSP-1.
authors.affiliation: Swiss Tropical Institute, Molecular Immunology, Socinstrasse 57, CH 4002 Basel, Switzerland.
authors.forename: Max
authors.initials: M
authors.lastname: Bastian
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Lozano
authors.forename: Manuel Elkin
authors.initials: ME
authors.lastname: Patarroyo
authors.forename: Gerd
authors.initials: G
authors.lastname: Pluschke
authors.forename: Claudia A
authors.initials: CA
authors.lastname: Daubenberger
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D000939:Epitopes / Q000276:immunology*; D006682:HLA-DP Antigens / Q000276:immunology; D006684:HLA-DR Antigens / Q000276:immunology; D006801:Humans; D017780:Malaria Vaccines / Q000276:immunology; D020066:Merozoite Surface Protein 1 / Q000276:immunology*; D010455:Peptides / Q000276:immunology*; D010963:Plasmodium falciparum / Q000276:immunology*
chemical_list: D000939:Epitopes; D006682:HLA-DP Antigens; D006684:HLA-DR Antigens; D017780:Malaria Vaccines; D020066:Merozoite Surface Protein 1; D010455:Peptides