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. ? ? ?
|Richards, Katherine A; Chaves, Francisco A; Alam, Shabnam et al. (2012) Trivalent inactivated influenza vaccines induce broad immunological reactivity to both internal virion components and influenza surface proteins. Vaccine 31:219-25|
|Chaves, Francisco A; Lee, Alvin H; Nayak, Jennifer L et al. (2012) The utility and limitations of current Web-available algorithms to predict peptides recognized by CD4 T cells in response to pathogen infection. J Immunol 188:4235-48|
|Nayak, Jennifer L; Sant, Andrea J (2012) Loss in CD4 T-cell responses to multiple epitopes in influenza due to expression of one additional MHC class II molecule in the host. Immunology 136:425-36|
|Richards, Katherine A; Chaves, Francisco A; Sant, Andrea J (2009) Infection of HLA-DR1 transgenic mice with a human isolate of influenza a virus (H1N1) primes a diverse CD4 T-cell repertoire that includes CD4 T cells with heterosubtypic cross-reactivity to avian (H5N1) influenza virus. J Virol 83:6566-77|