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Here we used a live attenuated<jats:named-content content-type=\"genus-species\">Salmonella enterica<\/jats:named-content>serovar Typhi strain to create a bivalent mucosal plague vaccine that produces both the protective F1 capsular antigen of<jats:named-content content-type=\"genus-species\">Yersinia pestis<\/jats:named-content>and the LcrV protein required for secretion of virulence effector proteins. To reduce the metabolic burden associated with the coexpression of F1 and LcrV within the live vector, we balanced expression of both antigens by combining plasmid-based expression of F1 with chromosomal expression of LcrV from three independent loci. The immunogenicity and protective efficacy of this novel vaccine were assessed in mice by using a heterologous prime-boost immunization strategy and compared to those of a conventional strain in which F1 and LcrV were expressed from a single low-copy-number plasmid. The serum antibody responses to lipopolysaccharide (LPS) induced by the optimized bivalent vaccine were indistinguishable from those elicited by the parent strain, suggesting an adequate immunogenic capacity maintained through preservation of bacterial fitness; in contrast, LPS titers were 10-fold lower in mice immunized with the conventional vaccine strain. Importantly, mice receiving the optimized bivalent vaccine were fully protected against lethal pulmonary challenge. These results demonstrate the feasibility of distributing foreign antigen expression across both chromosomal and plasmid locations within a single vaccine organism for induction of protective immunity.<\/jats:p>","DOI":"10.1128\/iai.02443-14","type":"journal-article","created":{"date-parts":[[2014,10,21]],"date-time":"2014-10-21T06:28:29Z","timestamp":1413872909000},"page":"161-172","update-policy":"http:\/\/dx.doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":19,"title":["A Bivalent Typhoid Live Vector Vaccine Expressing both Chromosome- and Plasmid-Encoded Yersinia pestis Antigens Fully Protects against Murine Lethal Pulmonary Plague Infection"],"prefix":"10.1128","volume":"83","author":[{"given":"James E.","family":"Galen","sequence":"first","affiliation":[{"name":"Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, Maryland, USA"},{"name":"Division of Geographic Medicine, Department of Medicine, University 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