Characterization and protective efficacy of type three secretion proteins as a broadly protective subunit vaccine against Salmonella enterica serovars

Non-typhoidal Salmonella enterica serotypes (NTS) are the leading cause of hospitalization and death due to foodborne illnesses. NTS are the costliest of the foodborne pathogens and cause ∼$4 billion annually in healthcare costs. In Africa, new invasive NTS are the leading cause of bacteremia especially in HIV-positive children and adults. Current vaccines against S. enterica are not broadly protective and most are directed at the typhoid causing serotypes, not the NTS. All S. enterica require two type III secretion systems (T3SS) for virulence. The T3SS needle tip protein and the first translocator are localized to the T3SS needle tip and are required for pathogenesis of S. enterica Collectively they are 95-98% conserved at the amino acid sequence level among all S. enterica The Salmonella pathogenicity island-1 or -2 tip and first translocator proteins were genetically fused to produce the S1 and S2 fusion proteins, respectively, as potential vaccine candidates. S1 and S2 were then characterized using spectroscopic techniques to understand their structural and biophysical properties. Formulated at the proper pH, S1, S2 or S1S2, admixed with adjuvant, was used to immunize mice followed by a lethal challenge with S. Typhimurium or S. Enteritidis. The S1S2 formulation provided the highest protective efficacy, thus demonstrating that an S1S2 subunit vaccine can provide broad, serotype independent protection, possibly against all S. enterica serotypes. Such a finding would be transformative in improving human health.