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Linking the Ii-Key functional group LRMK, through a simple polymethylene linker, to the melanoma gp100(48-58) MHC class II epitope significantly enhances the vaccine response to that epitope in DR4-IE transgenic mice. A homologous series of Ii-Key/gp100(46-58) hybrids was synthesized to test the influence of spacer length (between Ii-Key and the gp100(48-58) epitope) on in vivo enhancement of gp100(48-58)-specific CD4+ T-lymphocyte responses. As measured by IFN-γ and IL-4 ELISPOT cytokine assays, the most effective vaccine hybrid was the one with a shorter linker between Ii-Key and the epitope. Mechanistic reasons for this observation are considered. This structure-activity relationship was seen with bulk and CD4+ purified T cells, and both primary and secondary in vitro restimulation assays. CFA augmented the IFN-γ response and to a lesser extent the IL-4 response. CpG enhanced a strong IFN-γ response, with a negligible IL-4 response. The 3- to 5-times enhancement of the total ELISPOT responses (number of spots × mean spot area) observed after vaccination with peptides consisting of an MHC class II epitope engineered into an Ii-Key hybrid indicates a potent vaccine effect. Such constructs can be applied to many diagnostic and therapeutic uses.