Start Date: Aug 01, 2008
End Date: Jul 31, 2013
The structural requirements for induction of memory/effector CD4+ T lymphocytes, high titer IgG2, and protective immunity will be tested using the surface protein immunogen with either intact intermolecular linkages (cross-linked) or disrupted linkages (cross-linked then reduced). Mapping the B and T cell immunogenicity of protein partners within the cross-linked complex will define the minimal contributions required for protection. This is essential as the minimal immunogen will be more amenable to both standardization and development of low-cost vaccine. To ensure that the epitopes required for immunity are broadly represented among currently transmitted strains (rather than only “historical” strains isolated between 1950 and 1995), both outbreak and endemic strains will be isolated, genotyped, and the sequences of the relevant immunogenic proteins determined by targeted sequencing of their encoded genes. The strains will be isolated from endemic regions in United States and from regions in Mexico that export cattle to the U.S. The relevance of strain-specific polymorphisms to protective immunity and vaccine efficacy will be determined using CD4+ T lymphocytes and IgG2 antibody from immunized animals and immunologic differences confirmed by vaccine trials with heterologous strain challenge.