| Summary: | The etiologic agent of plague, <i>Yersinia pestis</i>, is a globally distributed pathogen which poses both a natural and adversarial threat. Due largely to the rapid course and high mortality of pneumonic plague, vaccines are greatly needed. Two-component protein vaccines have been unreliable and potentially vulnerable to vaccine resistance. We evaluated the safety and efficacy of eight live <i>Y. pestis</i> strains derived from virulent strains CO92 or KIM6+ and mutated in one or more virulence-associated gene(s) or cured of plasmid pPst. Stringent, single-dose vaccination allowed down-selection of the two safest and most protective vaccine candidates, CO92 mutants <i>pgm</i>- pPst- and Δ<i>yscN</i>. Both completely protected BALB/c mice against subcutaneous and aerosol challenge with <i>Y. pestis</i>. Strain CD-1 outbred mice were more resistant to bubonic (but not pneumonic) plague than BALB/c mice, but the vaccines elicited partial protection of CD-1 mice against aerosol challenge, while providing full protection against subcutaneous challenge. A Δ<i>yscN</i> mutant of the nonencapsulated C12 strain was expected to display antigens previously concealed by the capsule. C12 Δ<i>yscN</i> elicited negligible titers to F1 but comparable antibody levels to whole killed bacteria, as did CO92 Δ<i>yscN</i>. Although one dose of C12 Δ<i>yscN</i> was not protective, vaccination with two doses of either CO92 Δ<i>yscN,</i> or a combination of the Δysc<i>N</i> mutants of C12 and CO92, protected optimally against lethal bubonic or pneumonic plague. Protection against encapsulated <i>Y. pestis</i> required inclusion of F1 in the vaccine and was associated with high anti-F1 titers.
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