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Rewiring of one carbon metabolism in Salmonella serves as an excellent live vaccine against systemic salmonellosis

Datey, Akshay, Shreenivas, Meghanashree, Chandrasekharan, Giridhar, Joseph, Jeswin, Sah, Shivjee, Aluri, Srinivas, Saha, Sankhanil, Varshney, Umesh, Chakravortty, Dipshikha
Vaccine 2018 v.36 no.50 pp. 7715-7727
Neisseria meningitidis, Salmonella Typhimurium, animal models, antibodies, blood serum, carbon metabolism, cytokines, enzymes, genes, humans, live vaccines, morbidity, mortality, neonates, pathogens, pregnancy, subunit vaccines, typhoid fever, vaccination, virulence, young adults
Live attenuated vaccines are superior to the killed or subunit vaccines. We designed a Salmonella Typhimurium strain by deleting folD gene (encoding methylenetetrahydrofolate dehydrogenase-cyclohydrolase) in the presence of a heterologous fhs gene (encoding formyltetrahydrofolate synthetase) and tested its vaccine potential under stringent conditions of lethal and sub-lethal challenges with virulent Salmonella in the murine model. The efficacy of the vaccine in conferring protection against Salmonella infection was determined in a wide range of host conditions of systemic infection, corresponding to human young adults, neonates, geriatric age and, importantly, to the immune compromised state of pregnancy. The standardized vaccination regime comprised a primary dose of 104 CFU/animal followed by a booster dose of 102 CFU/animal on day 7. Challenge with the virulent pathogen was done at day 7 post-administration of the booster. Subsequently, the mortality, morbidity, systemic colonization, antibody response and cytokine profiling were determined. The vaccinated cohort showed a strong protection against virulent pathogen in all models tested. The serum anti-Salmonella antibody titers and cytokine levels were significantly higher in the vaccinated cohort compared to the mock vaccinated cohort. Thus, we report the development and validation of a live attenuated vaccine candidate conferring excellent protection against Salmonellosis and typhoid fever.