Characterization and Protective Efficacy of Type III Secretion Proteins as a Broadly Protective Subunit Vaccine against Salmonella enterica Serotypes

Abstract

Nontyphoidal 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 health care costs. In Africa, new invasive NTS are the leading cause of bacteremia, especially in HIV-positive children and adults. Current vaccines against are not broadly protective and most are directed at the typhoid-causing serotypes, not the NTS. All strains 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 Collectively they are 95 to 98% conserved at the amino acid sequence level among all strains. The 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 S1 plus S2 (S1S2), admixed with adjuvant, was used to immunize mice followed by a lethal challenge with serotype Typhimurium or serotype 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 serotypes. Such a finding would be transformative in improving human health.

Animal Models of Type III Secretion System-Mediated Pathogenesis

“…This section covers selected in vivo techniques to study the T3SS. Mice are the most common rodent used to study T3SS pathogenesis [35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50]. They are small, inexpensive, and well described in comparison to other models.…”

“…Vaccination studies are commonly done in mice [40,42,49], rabbits [65,66], cattle [81], and primates [86,91,93]. These studies can demonstrate the power of inhibiting the T3SS by using antibodies that recognize T3SS effectors or structural components.…”

Vaccines against gastroenteritis, current progress and challenges

“…However, no fecal IgA or antigen-specific IgA secreting cells in spleen or bone marrow were detected from the immunized mice. 270…”

Promises and Challenges of the Type Three Secretion System Injectisome as an Antivirulence Target

“…Increased protection is observed when flagellin is added to a vaccine against Salmonella T3SS protein SseB (74). A subunit vaccine against Salmonella consisting of two components, S1 (a genetic fusion of SPI-1 translocon proteins SipB and SipD) and S2 (a genetic fusion of SPI-2 proteins SseB and SseC) elicits strong IgG titers to all four proteins in mice (75). These mice are significantly protected against challenge with S. typhimurium and S. enteritidis and experience reduced cecal inflammation (75).…”