title: A rational strategy to design multiepitope immunogens based on multiple Th lymphocyte epitopes.
abstract: Four HLA-DR-restricted HIV-derived Th lymphocyte (HTL) epitopes cross-reactive with the murine I-A(b) class II molecule were used to evaluate different vaccine design strategies to simultaneously induce multiple HTL responses. All four epitopes were immunogenic in H-2(b) mice, demonstrating the feasibility of murine models to evaluate epitope-based vaccines destined for human use. Immunization with a pool of peptides induced responses against all four epitopes; illustrating immunodominance does not prevent the induction of balanced multispecific responses. When different delivery systems were evaluated, a multiple Ag peptide construct was found to be less efficient than a linear polypeptide encompassing all four epitopes. Further characterization of linear polypeptide revealed that the sequential arrangement of the epitopes created a junctional epitope with high affinity class II binding. Disruption of this junctional epitope through the introduction of a GPGPG spacer restored the immunogenicity against all four epitopes. Finally, we demonstrate that a GPGPG spacer construct can be used to induce HTL responses by either polypeptide or DNA immunization, highlighting the flexibility of the approach.
authors.affiliation: Epimmune, San Diego, CA 92121, USA. blivingston@epimmune.com
authors.forename: Brian
authors.initials: B
authors.lastname: Livingston
authors.forename: Claire
authors.initials: C
authors.lastname: Crimi
authors.forename: Mark
authors.initials: M
authors.lastname: Newman
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Higashimoto
authors.forename: Ettore
authors.initials: E
authors.lastname: Appella
authors.forename: John
authors.initials: J
authors.lastname: Sidney
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sette
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018984:Epitopes, T-Lymphocyte; D006678:HIV / Q000276:immunology*; D006684:HLA-DR Antigens / Q000276:immunology; D006801:Humans; D007114:Immunization; D051379:Mice; D008969:Molecular Sequence Data; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D014612:Vaccines / Q000276:immunology*; D019444:Vaccines, DNA / Q000276:immunology
chemical_list: D018984:Epitopes, T-Lymphocyte; D006684:HLA-DR Antigens; D014612:Vaccines; D019444:Vaccines, DNA