A rational strategy to design multiepitope immunogens based on multiple Th lymphocyte epitopes.
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.
Livingston
Brian
B
Epimmune, San Diego, CA 92121, USA. blivingston@epimmune.com
Crimi
Claire
C
Newman
Mark
M
Higashimoto
Yuichiro
Y
Appella
Ettore
E
Sidney
John
J
Sette
Alessandro
A
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
D018984:Epitopes, T-Lymphocyte; D006684:HLA-DR Antigens; D014612:Vaccines; D019444:Vaccines, DNA