The dissemination of Theileria parva immortalized bovine lymphoblasts into lymphoid and nonlymphoid tissues results in East Coast Fever a disease that continues to ravage cattle herds owned by resource poor small holder farmers and pastoralists throughout eastern, central, and southern Africa. The shortcomings of available control options are exemplified by failing acaricides and chemotherapeutics, and the technical and operational inadequacies of the live vaccination regime termed infection and treatment method (ITM). These constraints have provided impetus towards the development of subunit vaccines intended to render genetically diverse out-bred cattle populations immune to challenge by antigenically distinct parasites in the field throughout the endemic areas.Schizont antigens complexed with cattle class I MHC induce CD8+ cytotoxic T-lymphocytes (CTLs) that are the major effectors for immune control of T. parva. However, at present, there is insufficient information to predict the constraints to recombinant vaccine development based on induction of protective CTLs that may be imposed by functional divergence within cattle class I MHC genes. The first of the two broad studies described herein, utilized amplicon-based next generation sequencing combined with rigorous read processing algorithms to obtain reliable class I MHC genotypes from a field population of African native Bos taurus (Ankole). The study then leveraged progress in 'reverse immunology' to infer the extent of functional difference among the class I MHC alleles expressed by Ankole cattle as well as by exotic (Holstein) cattle. Finally, the study sought to ascertain if the dissimilarities seen in the in silico predictions of class I MHC peptide binding specificities between the two taurine lineages could be corroborated by ex vivo tests assaying cytokine responses to defined T. parva antigens.The major findings from the first study included: (i) the identification of 18 novel cattle class I MHC allelic sequences in Ankole cattle, (ii) the evidence of positive selection for sequence diversity including in residues that predominantly interact with peptides in Ankole class I MHC, (iii) the evidence from in silico functional analysis of peptide binding specificities that are largely distinct between the two breeds and (iv) the demonstration that CD8+ T-cells derived from Ankole cattle that were seropositive for T. parva did not recognize vaccine candidate antigens originally identified in Holstein cattle breeds. This includes the immunodominant Tp1 which is currently the main focus of ongoing ECF recombinant vaccine trials. Taken together, the data clearly demonstrates that overlap between the peptide binding specificities of cattle class I MHC molecules is likely to be largely confined to alleles belonging to the same breed. These differences have the implication that a number of different antigens/epitopes will need to be incorporated in a CD8+ T-cell based recombinant antigen cocktail vaccine to provide broad coverage.In addition to the