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A Rational Strategy to Design Multiepitope Immunogens Based on Multiple Th Lymphocyte Epitopes¹

Brian Livingston^2,*, Claire Crimi^*, Mark Newman^*, Yuichiro Higashimoto, Ettore Appella, John Sidney^* and Alessandro Sette^*

^* Epimmune, San Diego, CA 92121; and Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892

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.

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