Heat-Stable Enterotoxin of EnterotoxigenicEscherichia colias a Vaccine Target

Abstract

5Enterotoxigenic Escherichia coli (ETEC) is responsible for 280 million to 400 million episodes of diarrhea and about 380,000 deaths annually. Epidemiological data suggest that ETEC strains which secrete heat-stable toxin (ST), alone or in combination with heat-labile toxin (LT), induce the most severe disease among children in developing countries. This makes ST an attractive target for inclusion in an ETEC vaccine. ST is released upon colonization of the small intestine and activates the guanylate cyclase C receptor, causing profuse diarrhea. To generate a successful toxoid, ST must be made immunogenic and nontoxic. Due to its small size, ST is nonimmunogenic in its natural form but becomes immunogenic when coupled to an appropriate large-molecular-weight carrier. This has been successfully achieved with several carriers, using either chemical conjugation or recombinant fusion techniques. Coupling of ST to a carrier may reduce toxicity, but further reduction by mutagenesis is desired to obtain a safe vaccine. More than 30 ST mutants with effects on toxicity have been reported. Some of these mutants, however, have lost the ability to elicit neutralizing immune responses to the native toxin. Due to the small size of ST, separating toxicity from antigenicity is a particular challenge that must be met. Another obstacle to vaccine development is possible cross-reactivity between anti-ST antibodies and the endogenous ligands guanylin and uroguanylin, caused by structural similarity to ST. Here we review the molecular and biological properties of ST and discuss strategies for developing an ETEC vaccine that incorporates immunogenic and nontoxic derivatives of the ST toxin.

Colonization Factors in Enterotoxigenic Escherichia coli Strains in Travelers to Mexico, Guatemala, and India Compared with Children in Houston, Texas

“…This is important because ST is poorly antigenic or nonantigenic, shares epitope homology with the human endogenous peptides of the guanylin family, and has yet to be incorporated into a vaccine construct; however, efforts of with ST-toxoid fusions are actively being developed. 19,20 Our finding that ST as the most common ETEC toxin is in agreement with a systematic review carried out by Isidean and others 6 In their study among travelers acquiring diarrhea in Latin America, the proportion of ETEC expressing ST was 67% and for travelers in south Asia it was 56%. In our study, we found that 56% of ETEC identified were ST-producing strains among travelers to Mexico, Guatemala, and India.…”

Novel Heat-Stable Enterotoxin (STa) Immunogen Based on Cationic Nanoliposomes: Preparation, Characterization and Immunization

“…Given the fact the STa is poor immunogenic (<2000 Daltons) [5,6], hence the first step toward triggering an appropriate immune response against STa is to couple it to an appropriate carrier. Several strategies have been investigated to make STa immunogenic either through chemical conjugation [6,[31][32][33] or recombinant fusion protein [7,[34][35][36][37][38].…”

“…Therefore, the development of a subtle vaccine against ETEC diarrhea is deemed necessary for both human and livestock health as well. However, STa presents a problematic antigen owing to its poor immunogenic nature caused by its small molecular weight which is less than 2 KDa [5,6].…”

A Modular Approach to Assembly of Totally Synthetic Self-adjuvanting Lipopeptide-based Vaccines Allows Conformational Epitope Building

“…STh is an 18-mer peptide and is non-immunogenic when administered alone (15). Previous reports have indicated that when chemically coupled or genetically fused to a protein carrier the ST-protein conjugate is able to elicit anti-ST antibody, and in some instances, the antiserum is able to neutralize the toxic activity of ST.…”

“…This toxin is secreted by pathogenic strains of E. coli and causes diarrhea especially among children in developing countries. Antibodies directed to ST can neutralize the toxin and prevent the occurrence of diarrhea (15), although ST itself is not immunogenic. (ii) Gonadotrophin-releasing hormone also known as luteinizing hormone-releasing hormone (LHRH) with the sequence HWSYGLRPG is secreted by the hypothalamus and initiates a cascade of endocrine events that govern reproduction.…”