The major goal of the experiments outlined in this R21 proposal is to promote heterosubtypic immunity to influenza virus infection. Influenza is a significant human pathogen for which there is no available vaccine1 that promotes persistent and effective immunity. This is a particularly urgent objective of late because of the emergence of a highly pathogenic H5N1 strain of avian influenza that has passed to humans, creating a potential threat of a pandemic. Recently, our laboratory has developed a novel and successful strategy to manipulate immunodominance in CD4 T cell responses. In this proposal, we wish to use this strategy to explore whether intentional focus of the CD4 T cell response toward epitopes shared among subtypes of influenza, particularly those expressed within the H5 subtype, will promote protective heterosubtypic immunity. Because of the direct implication of these studies on human vaccine design, we will perform these experiments using peptides presented by human HLA-DR molecules and DR1-transgenic mice. We will derive novel HA peptide-containing protein constructs to drive intentional focus of the CD4 T cell response towards hemagglutinin epitopes that are highly conserved among serologically distinct HA subtypes. Specific Aim 1: Identification of immunodominant DR1-restricted CD4 T cell epitopes to influenza HA. Specific Aim 2: Design and utilize kinetic stability variants of HA-derived peptides to promote immunodominance. Specific Aim 3. Promoting focus of the CD4 T cell responses toward conserved epitopes and protection to virus challenge. [unreadable] [unreadable] [unreadable]