Evaluation of Regulated Delayed Attenuation Strategies for Salmonella enterica Serovar Typhi Vaccine Vectors in Neonatal and Infant Mice

We developed regulated delayed attenuation strategies forSalmonella vaccine vectors. In this study, we evaluated the combination of these strategies in recombinant attenuatedSalmonella enterica serovar Typhi andSalmonella enterica serovar Typhimurium vaccine vectors with similar genetic backgroundsin vitro andin vivo . Our goal is to develop a vaccine to preventStreptococcus pneumoniae infection in newborns; thus, all strains delivered a pneumococcal antigen PspA and the impact of maternal antibodies was evaluated. The results showed that all strains with the regulated delayed attenuated phenotype (RDAP) displayed an invasive ability stronger than that of theS. Typhi vaccine strain, Ty21a, but weaker than that of their corresponding wild-type parental strains. The survival curves of different RDAP vaccine vectorsin vitro andin vivo exhibited diverse regulated delayed attenuation kinetics, which was different fromS. Typhi Ty21a and the wild-type parental strains. Under the influence of maternal antibody, the persistence of theS. Typhimurium RDAP strain displayed a regulated delayed attenuation trend in nasal lymphoid tissue (NALT), lung, and Peyer's patches, while the persistence ofS. Typhi RDAP strains followed the curve only in NALT. The bacterial loads ofS. Typhi RDAP strains were lower in NALT, lung, and Peyer's patches in mice born to immune mothers than in those born to naive mothers. In accordance with these results, RDAP vaccine strains induced high titers of IgG antibodies against PspA and againstSalmonella lipopolysaccharides. Immunization of mothers withS. Typhi RDAP strains enhanced the level of vaginal mucosal IgA, gamma interferon (IFN-γ), and interleukin 4 (IL-4) and resulted in a higher level of protection againstS. pneumoniae challenge.