Many important Gram-negative pathogens that cause disease in humans and food production animals have specifically evolved to colonize and reside in the mucosal surfaces of their hosts. A key enabling factor in the survival and the pathogenesis of these bacteria is the bacterial transferrin receptor, which is used by these organisms to acquire iron, an essential micronutrient, from their host environment. The bacterial transferrin receptor is composed of the transferrin binding protein A and B (TbpA and TbpB), which bind exclusively to host protein transferrin and thus, limits the niche for these bacteria exclusively to their host species. TbpA is an outer, transmembrane TonB-dependent transporter, which enables the internalization of iron into the periplasm. TbpB is a surface exposed lipoprotein anchored to the bacterial membrane and aids in capturing iron loaded transferrin in the extracellular milieu. The bacterial transferrin receptor has been considered as a prospective vaccine antigen against these pathogens hence the objective of this thesis is to evaluate these proteins as an antigen. Previous studies have shown that when a TbpB mutant from porcine pathogen Glaesserella parasuis engineered to be defective in binding to porcine transferrin (Y167A TbpB) was used as a vaccine antigen, superior protection was observed in a swine model compared to the wildtype TbpB control. For the first aim, findings from this thesis demonstrated that a murine model of sepsis can be used to evaluate different TbpB mutants, providing a tool to screen different mutants prior to evaluating in a swine model. For the second aim, new TbpB mutants defective in binding to porcine transferrin were generated and evaluated as vaccine antigens. For the third aim, the cross-reactivity of immunizations with either single or multiple TbpB antigens is explored. A combined vaccine formulation with two antigens elicited a broadly cross-reactive response raising the possibility that a final TbpB based vaccine limited to these two antigens may be sufficient in providing protection against the entire repertoire of TbpB variants. Finally, a method for generating chimeric/hybrid antigens using TbpB based scaffolds to display extracellular loops from membrane proteins like TbpA in order to take advantage of TbpA as a vaccine antigen is discussed. Overall, the findings of this thesis adds to our understanding of the bacterial transferrin receptor as a vaccine antigen and brings us closer to the final, optimal vaccine composition for eliciting efficacious and broadly cross-protective coverage.