| Summary: | Nontyphoidal <i>Salmonella enterica</i> (NTS) is a leading cause of foodborne illness worldwide, including in the United States, where infants show the highest incidence amongst all age groups. <i>S. enterica</i> serovar Typhimurium is one of the most frequently isolated serovars from NTS infections. We have developed several candidate live-attenuated <i>S.</i> Typhimurium vaccines to prevent NTS infection. The goal of the current study was to assess three live <i>S.</i> Typhimurium vaccine strains (CVD 1921, CVD 1921 ∆<i>htrA</i> and CVD 1926, which have two, three and four gene deletions, respectively) with various levels of reactogenicity and immunogenicity in infant BALB/c mice to predict how they would perform following peroral immunization of infants. We first tested intranasal immunization of 14-day-old mice with three doses delivered at 1-week intervals and evaluated antibody responses and protection against lethal infection with wild-type <i>S.</i> Typhimurium. The vaccines were administered to 14-day-old mice via the peroral route at 1- or 2-week intervals and to 28-day-old mice at 2-week intervals. The three vaccine strains were immunogenic following intranasal immunization of infant mice with vaccine efficacies of 80% (CVD 1921), 63% (CVD 1921 ∆<i>htrA</i>) and 31% (CVD 1926). In contrast, peroral immunization of 14-day-old mice yielded much poorer protection against lethal infection and only immunization of 28-day-old mice at 2-week intervals showed similar protective capacity as intranasal administration (CVD 1921: 83%, CVD 1921 ∆<i>htrA:</i> 43% and CVD 1926: 58%). CVD 1921 was consistently more protective than both CVD 1921 ∆<i>htrA</i> and CVD 1926, regardless of the route of vaccination, immunization schedule and age of mice. Anti-LPS serum IgG responses were similar between the three strains and did not correlate with protection. Due to previously observed reactogenicity of CVD 1921, CVD 1921 ∆<i>htrA</i> and CVD 1926 are our preferred vaccines, but these data show that further improvements would need to be made to achieve suitable protection in young infants when using peroral immunization.
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