Vaccine for Enterotoxigenic Escherichia coli Based on Synthetic Heat-Stable Toxin Crossed-Linked to the B Subunit of Heat-Labile Toxin

Klipstein, Frederick A.; Engert, R F; Clements, John D.; Boughten, Richard A.

doi:10.1093/infdis/147.2.318

Cited by 45 publications

(44 citation statements)

References 36 publications

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“…In the next step toward developing an ST vaccine, synthetic ST was conjugated to the B subunit of the heat-labile enterotoxin (LT-B) and shown to be immunogenic in both rats and rabbits. These immunized animals were protected in challenge experiments with ST and ST-producing ETEC (22,23,27). Interestingly, the chemical coupling of ST to LT-B reduced the toxicity more than 600-fold (22).…”

Section: St Vaccinologymentioning

confidence: 99%

Heat-Stable Enterotoxin of EnterotoxigenicEscherichia colias a Vaccine Target

et al. 2010

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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.

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Section: St Vaccinologymentioning

confidence: 99%

Heat-Stable Enterotoxin of EnterotoxigenicEscherichia colias a Vaccine Target

et al. 2010

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“…Because of their small size, STa enterotoxins are nonimmunogenic by themselves but can behave as haptens. Hence, a promising approach for development of immunoprophylactic agents against diarrhea caused by STa is the coupling of this protein to larger carrier molecules by chemical (5,23,24) or genetic (4,(18)(19)(20) means. We have studied the possibility of using the E. coli OmpC outer membrane protein (12) as a carrier protein for STa.…”

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confidence: 99%

Fusion of genes encoding Escherichia coli heat-stable enterotoxin and outer membrane protein OmpC

et al. 1989

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The OmpC outer membrane protein of Escherichia coli was used as a carrier molecule for the nonimmunogenic heat-stable enterotoxin STa. Two fragments of different lengths of the gene encoding STa were fused in vitro to the 3' terminus of the truncated ompC gene. The resulting OmpC-STa hybrid proteins could be detected by L-[35S]cysteine labeling, and they were processed and thus exported. All synthesized hybrid protein remained cell bound and was found by fractionation mainly in the periplasm. Immunoblot analysis showed that the hybrid proteins reacted in vitro both with anti-OmpC and anti-STa antibodies, and immunization of rabbits evoked an antibody response to either of these proteins.

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“…Studies to date have demonstrated that it is possible, either by chemical conjugation of ST peptides to carrier molecules [35,36,37,38,39], or by genetic construction of ST-fusion proteins [40,41,42,43,44,45], to induce antibodies to ST. Earlier experiments with a modified ST molecule conjugated to heat-labile toxin B subunit (LT-B) provided compelling evidence that it is possible to generate neutralizing antibodies against ST in humans.…”

Section: Strategies To Neutralize Toxin Deliverymentioning

confidence: 99%

Designing Vaccines to Neutralize Effective Toxin Delivery by Enterotoxigenic Escherichia coli

Fleckenstein

Sheikh

2014

Toxins

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Enterotoxigenic Escherichia coli (ETEC) are a leading cause of diarrheal illness in developing countries. Despite the discovery of these pathogens as a cause of cholera-like diarrhea over 40 years ago, and decades of vaccine development effort, there remains no broadly protective ETEC vaccine. The discovery of new virulence proteins and an improved appreciation of the complexity of the molecular events required for effective toxin delivery may provide additional avenues to pursue in development of an effective vaccine to prevent severe diarrhea caused by these important pathogens.

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Vaccine for Enterotoxigenic Escherichia coli Based on Synthetic Heat-Stable Toxin Crossed-Linked to the B Subunit of Heat-Labile Toxin

Cited by 45 publications

References 36 publications

Heat-Stable Enterotoxin of EnterotoxigenicEscherichia colias a Vaccine Target

Heat-Stable Enterotoxin of EnterotoxigenicEscherichia colias a Vaccine Target

Fusion of genes encoding Escherichia coli heat-stable enterotoxin and outer membrane protein OmpC

Designing Vaccines to Neutralize Effective Toxin Delivery by Enterotoxigenic Escherichia coli

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