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While nontyphoidalSalmonella (NTS) has long been recognized as a cause of self-limited gastroenteritis, it is becoming increasingly evident that multiple-antibiotic-resistant strains are also emerging as important causes of invasive bacteremia and focal infections, resulting in hospitalizations and deaths. We have constructed attenuatedSalmonella enterica serovar Typhimurium andSalmonella enterica serovar Enteritidis strains that can serve as live oral vaccines and as “reagent strains” for subunit vaccine production in a safe and economical manner. Prototype attenuated vaccine strains CVD 1921 and CVD 1941, derived from the invasive wild-type strainsS. Typhimurium I77 andS. Enteritidis R11, respectively, were constructed by deletingguaBA , encoding guanine biosynthesis, andclpP , encoding a master protease regulator. TheclpP mutation resulted in a hyperflagellation phenotype. An additional deletion infliD yielded reagent strains CVD 1923 and CVD 1943, respectively, which export flagellin monomers. Oral 50% lethal dose (LD50 ) analyses showed that the NTS vaccine strains were all highly attenuated in mice. Oral immunization with CVD 1921 or CVD 1923 protected mice against lethal challenge with wild-typeS. Typhimurium I77. Immunization with CVD 1941 but not CVD 1943 protected mice against lethal infection withS. Enteritidis R11. Immune responses induced by these strains included high levels of serum IgG anti-lipopolysaccharide (LPS) and anti-flagellum antibodies, with titers increasing progressively during the immunization schedule. SinceS. Typhimurium andS. Enteritidis are the most common NTS serovars associated with invasive disease, these findings can pave the way for development of a highly effective, broad-spectrum vaccine against invasive NTS.

Engineering and Preclinical Evaluation of Attenuated Nontyphoidal Salmonella Strains Serving as Live Oral Vaccines and as Reagent Strains