Abstract
Acute diarrhea disease caused by bacterial infections is a major global health problem. Enterotoxigenic Escherichia coli (ETEC) is one of the top causes of diarrhea-associated morbidity and mortality in young children and travelers to low-income countries. There are currently no licensed vaccines for ETEC. Induction of immunity at the site of entry of the bacteria is key to prevent infection. Current approaches to ETEC vaccines include a less toxic mutant form of E. coli heat-labile toxin (double-mutant heat-labile enterotoxin -dmLT-) with both antigenic and immunostimulatory properties. U-Omp19 is a protease inhibitor from Brucella spp. with immunostimulatory properties that has been used as oral adjuvant. In this work, we use U-Omp19 as adjuvant in an oral vaccine formulation against ETEC containing dmLT in outbred and inbred mice. To evaluate antigen dose sparing by U-Omp19 three different immunization protocols with three different doses of dmLT were evaluated. We demonstrated that U-Omp19 co-delivery increases anti-LT IgA in feces using a mid-dose of dmLT following a prime-boost protocol (after one or two boosts). Oral immunization with U-Omp19 induced protection against LT challenge when co-formulated with dmLT in CD-1 and BALB/c mice. Indeed, there was a significant increase in anti-LT IgG and IgA avidity after a single oral administration of dmLT plus U-Omp19 in comparison with dmLT delivered alone. Interestingly, sera from dmLT plus U-Omp19 vaccinated mice significantly neutralize LT effect on intestine inflammation in vivo compared with sera from the group immunized with dmLT alone. These results demonstrate the adjuvant capacity of U-Omp19 to increase dmLT immunogenicity by the oral route and support its use in an oral subunit vaccine formulation against ETEC.
Highlights
Acute enteric infections causing diarrhea and gastroenteritis constitute a global public health problem with high mortality and morbidity, among children in low-income and lower middle-income countries
We have shown that protease inhibitor properties of U-Omp19 allow it to bypass the harsh environment of the gastrointestinal tract limiting co-administered Ag digestion and increasing Ag amount at immune inductive sites
We evaluated the immunogenicity and protective efficacy of an oral formulation containing U-Omp19 and double mutant heat-labile toxin LTR192G/ L211A (dmLT) as antigen in mice
Summary
Acute enteric infections causing diarrhea and gastroenteritis constitute a global public health problem with high mortality and morbidity, among children in low-income and lower middle-income countries. Diarrhea ranked ninth among causes of death for all ages, and fourth among infants, accounting for an estimated 499,000 deaths in children under 5 years old [1]. In developed countries where sanitation standards are usually higher, ETEC infection is rare. It remains a leading cause of travelers’ diarrhea which occurs in people visiting or returning from ETEC-endemic regions [3,4]. Epidemics of ETEC diarrhea have occurred during natural disasters, such as floods where the quality of drinking water and sanitation were drastically affected [5]
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