<span class="paragraphSection"><div class="boxTitle">Abstract</div><span style="font-style:italic;">Shigella sonnei</span> and <span style="font-style:italic;">Salmonella</span> Typhi cause significant morbidity and mortality. We exploited the safety record of the oral, attenuated <span style="font-style:italic;">S.</span> Typhi vaccine (Ty21a) by using it as a vector to develop a bivalent oral vaccine to protect against <span style="font-style:italic;">S. sonnei</span> shigellosis and typhoid fever. We recombineered the <span style="font-style:italic;">S. sonnei</span> form I O-antigen gene cluster into the Ty21a chromosome to create Ty21a-Ss, which stably expresses <span style="font-style:italic;">S. sonnei</span> form I O antigen. To enhance survivability in the acid environment of the stomach, we created an acid-resistant strain, Ty21a-AR-Ss, by inserting <span style="font-style:italic;">Shigella</span> glutaminase–glutamate decarboxylase systems coexpressed with <span style="font-style:italic;">S. sonnei</span> form I O-antigen gene. Mice immunized intranasally with Ty21a-AR-Ss produced antibodies against <span style="font-style:italic;">S. sonnei</span> and <span style="font-style:italic;">S.</span> Typhi, and survived lethal intranasal <span style="font-style:italic;">S. sonnei</span> challenge. This paves the way for proposed good manufacturing practices manufacture and clinical trials intended to test the clinical effectiveness of Ty21a-AR-Ss in protecting against <span style="font-style:italic;">S. sonnei</span> shigellosis and typhoid fever, as compared with the current Ty21a vaccine.</span>
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