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The vast majority of live attenuated typhoid vaccines are constructed from the Salmonella enterica serovar Typhi strain Ty2, which is devoid of a functioning alternative sigma factor, RpoS, due to the presence of a frameshift mutation. RpoS is a specialized sigma factor that plays an important role in the general stress response of a number of Gram-negative organisms, including Salmonella . Previous studies have demonstrated that this sigma factor is necessary for survival following exposure to acid, hydrogen peroxide, nutrient-limiting conditions, and starvation. In addition, studies with Salmonella enterica serovar Typhimurium and the mouse model of typhoid fever have shown that RpoS is important in colonization and survival within the infected murine host. We converted 4 clinically studied candidate typhoid vaccine strains derived from Ty2 [CVD908 -htrA , Ty800, and χ9639(pYA3493)] and the licensed live typhoid vaccine Ty21a (also derived from Ty2) to RpoS + and compared their abilities to withstand environmental stresses that may be encountered within the host to those of the RpoS - parent strains. The results of our study indicate that strains that contain a functional RpoS were better able to survive following stress and that they would be ideal for further development as safe, effective vaccines to prevent S . Typhi infections or as vectors in recombinant attenuated Salmonella vaccines (RASVs) designed to protect against other infectious disease agents in humans. The S . Typhi strains constructed and described here will be made freely available upon request, as will the suicide vector used to convert rpoS mutants to RpoS + . IMPORTANCE Recombinant attenuated Salmonella vaccines (RASVs) represent a unique prevention strategy to combating infectious disease because they utilize the ability of Salmonella to invade and colonize deep effector lymphoid tissues and deliver hetero- and homologous derived antigens at the lowest immunizing dose. Our recent clinical trial in human volunteers indicated that an RpoS + derivative of Ty2 was better at inducing immune responses than its RpoS - counterpart. In this study, we demonstrate that a functional RpoS allele is beneficial for developing effective live attenuated vaccines against S . Typhi or in using S . Typhi as a recombinant attenuated vaccine vector to deliver other protective antigens.

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Conversion of RpoS <sup>−</sup> Attenuated Salmonella enterica Serovar Typhi Vaccine Strains to RpoS <sup>+</sup> Improves Their Resistance to Host Defense Barriers

Conversion of RpoS − Attenuated Salmonella enterica Serovar Typhi Vaccine Strains to RpoS + Improves Their Resistance to Host Defense Barriers

Conversion of RpoS ⁻ Attenuated Salmonella enterica Serovar Typhi Vaccine Strains to RpoS ⁺ Improves Their Resistance to Host Defense Barriers