Pathogenic serovars of Salmonella enterica are the causative bacteria for typhoid fever and non-typhoidal salmonellosis, accounting for significant morbidity and mortality worldwide. Despite the disease burden and rising prevalence of antibiotic resistance, highly efficacious vaccines against Salmonella infections have yet to be developed. Much of the research to date has focused on targeting virulence factors or biosynthetic pathways for developing Salmonella live-attenuated vaccines (LAV). Many of these Salmonella LAV strains show variable potential for inducing protective immunity, however, the key factors that determine whether a vaccine is partially or fully protective remain to be elucidated.
Our laboratory has recently generated a novel carbon metabolic mutant of Salmonella enterica serovar Typhimurium (ΔeddΔpfkAΔpfkB), denoted S. Typhimurium TAS2010. Experimental infection with wild-type S. Typhimurium in C57BL/6 mice leads to typhoid-like systemic disease and mortality within 10 days. We observed that vaccination with TAS2010 conferred superior protection against wild-type S. Typhimurium infection compared to vaccination with the benchmark LAV strain, BRD509 (ΔaroA). In contrast to BRD509, vaccination with TAS2010 elicited heightened activation of multiple immune responses, including increased neutrophil recruitment, elevated production of cytokines such as IFN-γ, TNF-α and IL-6, and most importantly, enhanced activation of CD4+ T cells that are critical for antigen-specific immunity. The magnitude of immune activation is positively correlated with net bacterial load during the first two weeks post-vaccination, suggesting a fundamental tension between immunogenicity and safety in Salmonella LAV design. Ongoing studies will utilise the TAS2010 LAV and further investigate how CD4+ T cell responses can be modulated to confer enhanced protection. This work will most likely shed light on key determinants of immunity relevant for future development of efficacious Salmonella vaccines.