Current Applications and Immunological Considerations of Salmonella enterica Serovar Typhimurium as a Vaccine Vector

Live attenuated <i>Salmonella enterica</i> serovar Typhimurium has been investigated for decades as an orally delivered vaccine vector due to its ability to target the intestinal mucosa and engage both innate and adaptive immune responses. In humans, <i>S.</i> Typhimurium infection is largely restricted to the gastrointestinal tract, distinguishing it from <i>Salmonella Typhi</i> and providing a rationale for its use in mucosal vaccine strategies. In this review, we discuss the biological features of <i>S.</i> Typhimurium that support its use as a vaccine vector and summarize current understanding of the immune responses generated during wild-type infection, including innate activation and downstream T cell and B cell responses. We compare key biological differences between <i>Salmonella</i> Typhi and <i>S</i>. Typhimurium and outline emerging vector design strategies, including delayed attenuation and chromosomal integration of heterologous antigens. We then review applications of attenuated <i>S.</i> Typhimurium vectors targeting viral, bacterial, and parasitic pathogens, highlighting shared immunological outcomes and design principles across platforms. Finally, we discuss recent advances in vector engineering, including chromosomal integration of heterologous antigens, as well as remaining gaps in knowledge related to the durability of immune responses and translational considerations.