A Combined YopB and LcrV Subunit Vaccine Elicits Protective Immunity against Yersinia Infection in Adult and Infant Mice

Abstract

Yersinia enterocolitica causes a severe enteric infection in infants and young children. There is no vaccine approved for use in humans. We investigated the immunogenicity and protective capacity of Yersinia YopB, a conserved type III secretion system protein, alone or combined with LcrV in adult mice immunized intranasally. YopB or LcrV (5 mg) administered with the Escherichia coli double mutant heat-labile toxin (dmLT) adjuvant afforded modest (10-30%) protection against lethal Y. enterocolitica oral infection. The combination of YopB and LcrV (5 mg each) dramatically improved vaccine efficacy (70-80%). Additionally, it afforded complete protection against Y. pestis pulmonary infection. Immunization with YopB/LcrV+dmLT resulted in Ag-specific serum IgG, systemic and mucosal Ab-secreting cells, as well as IFN-g, TNF-a, IL-2, IL-6, IL-17A, and KC production by spleen cells. Serum Abs elicited by YopB/LcrV+dmLT had enhanced bactericidal and opsonophagocytic killing activity. After Y. enterocolitica challenge, YopB/LcrV+dmLT-vaccinated mice exhibited intact intestinal tissue, active germinal centers in mesenteric lymph nodes, IgG + and IgA + plasmablasts in the lamina propria, and Abs in intestinal fluid. On the contrary, complete tissue destruction and abscesses were seen in placebo recipients that succumbed to infection. Mice immunized as infants with YopB+dmLT or LcrV+dmLT achieved 60% protection against lethal Y. enterocolitica infection, and vaccine efficacy increased to 90-100% when they received YopB/LcrV+dmLT. YopB+dmLT also afforded substantial (60%) protection when administered intradermally to infant mice. YopB/LcrV+dmLT is a promising subunit vaccine candidate with the potential to elicit broad protection against Yersinia spp.

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.…”

“…These studies can demonstrate the power of inhibiting the T3SS by using antibodies that recognize T3SS effectors or structural components. One of the most notable instances of recent vaccine research occurred in the Pasetti laboratory [49]. They have developed a combined YopB and LcrV subunit vaccine that acts against Yersinia enterocolitica, a pathogen that causes severe enteric infection in young children and infants.…”

Evaluation of Three Candidate Live-Attenuated Salmonella enterica Serovar Typhimurium Vaccines to Prevent Non-Typhoidal Salmonella Infection in an Infant Mouse Model

“…The modest-to-excellent protection provided by intranasal compared to peroral delivery could be due to vaccine stability in the absence of gastric acid or interference from immune factors ingested with maternal milk. Subunit and bacterial-like particle vaccines against Yersinia enterocolitica and Shigella flexneri have shown significant VE when delivered to adult and infant mice via the intranasal route [42,43]. The improved VE observed when some doses were delivered post-weaning on the extended schedule or in 28-day-old mice may reflect the absence of maternal milk interference and age-associated increase in immune function.…”

Delivery of Heterologous Proteins, Enzymes, and Antigens via the Bacterial Type III Secretion System

“…Since its discovery, the T3SS has been implicated as a virulence factor utilized by certain Gram-negative pathogens such as enterohemorrhagic and enteropathogenic Escherichia coli (EHEC and EPEC, respectively) [10,18,19], Salmonella enterica serovar Typhimurium [20,21], Chlamydia spp. [22,23], and Yersinia pestis [24][25][26], the causative agent of the plague. Each year, these pathogens infect more than 2 million people in the United States [27][28][29][30].…”