Haemophilus parasuis is the causative agent of the Glässer's disease (GD), one of the most important bacterial diseases that affect young pigs worldwide. GD prevention based on vaccination is a major concern due to the limited cross-protection conferred by the inactivated whole cell vaccines used currently. In this study, vaccines based on two mutant recombinant proteins derived from transferrin binding protein B of H. parasuis (Y167A-TbpB and W176A-TbpB) were formulated and evaluated in terms of protection against lethal challenge using a serovar 7 (SV7) H. parasuis in a high susceptibility pig model. Our results showed that H. parasuis strain 174 (SV7) is highly virulent in conventional and colostrum-deprived pigs. The Y167A-TbpB and W176A-TbpB antigens were immunogenic in pigs, however, differences in terms of antigenicity and functional immune response were observed. In regard to protection, animals immunized with Y167A-TbpB antigen displayed 80% survival whereas the W176A-TbpB protein was not protective. In conjunction with previous studies, our results demonstrate, (a) the importance of testing engineered antigens in an in vivo pig challenge model, and, (b) that the Y167A-TbpB antigen is a promising antigen for developing a broad-spectrum vaccine against H. parasuis infection.