| Summary: | Susceptibility to brucellosis remains prevalent, even in herds vaccinated with conventional vaccines. Efforts are underway to develop an improved brucellosis vaccine, and possibly a universal vaccine, given that <i>Brucella</i> species are highly homologous. To this end, two <i>B. melitensis</i> mutants were developed, znBM-<i>lacZ</i> (znBMZ) and znBM-mCherry (znBM-mC), and were tested for their ability to confer systemic immunity against virulent <i>B. melitensis</i> challenge. To assess the extent of their attenuation, bone-marrow-derived macrophages and human TF-1 myeloid cells were infected with both mutants, and the inability to replicate within these cells was noted. Mice infected with varying doses of znBM-mC cleared the brucellae within 6–10 weeks. To test for efficacy against systemic disease, groups of mice were vaccinated once by the intraperitoneal route with either znBMZ or <i>B. abortus</i> S19 vaccine. Relative to the PBS-dosed mice, znBMZ vaccination greatly reduced splenic brucellae colonization by ~25,000-fold compared to 700-fold for S19-vaccinated mice. Not surprisingly, both znBMZ and S19 strains induced IFN-γ<sup>+</sup> CD4<sup>+</sup> T cells, yet only znBMZ induced IFN-γ<sup>+</sup> CD8<sup>+</sup> T cells. While both strains induced CD4<sup>+</sup> effector memory T cells (Tems), only znBMZ induced CD8<sup>+</sup> Tems. Thus, these results show that the described znBM mutants are safe, able to elicit CD4<sup>+</sup> and CD8<sup>+</sup> T cell immunity without a boost, and highly effective, rendering them promising vaccine candidates for livestock.
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