Recombinant cholera toxin B subunit and gene fusion proteins for oral vaccination

Sánchez, Jesús R.; Johansson, S.; Löwenadler, Björn; Svennerholm, Ann‐Mari; Holmgren, Jan

doi:10.1016/0923-2508(90)90137-f

Cited by 48 publications

(24 citation statements)

References 15 publications

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“…Detoxifying ST. Detoxification of ST can be achieved, at least in part, by genetic fusion or chemical conjugation, but it has often been combined with mutagenesis (2,35,39). Several mutants with effects on toxicity have been reported and are summarized in Fig.…”

Section: St Vaccinologymentioning

confidence: 99%

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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%

“…This study was followed by experiments where various ST-related fragments, including the full sequence of STh, were fused to the N and C termini of CT-B, (39). The obtained level of anti-ST antibodies only partially neutralized ST in challenge experiments with suckling mice.…”

Section: St Vaccinologymentioning

confidence: 99%

Heat-Stable Enterotoxin of EnterotoxigenicEscherichia colias a Vaccine Target

et al. 2010

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“…While it is generally accepted that the holotoxins are mucosal adjuvants, the actual adjuvanticity of the B subunits is questioned (11,13). However, there is evidence indicating that CTB and LTB can function as carriers for mucosal delivery of vaccine antigens (7,10,25,30,43,45,52) and possess some adjuvant activity (9,15,16,53,56).…”

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confidence: 99%

Immunogenicity of the B Monomer ofEscherichia coliHeat-Labile Toxin Expressed on the Surface ofStreptococcus gordonii

et al. 2000

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The B monomer of the Escherichia coli heat-labile toxin (LTB) was expressed on the surface of the human oral commensal bacterium Streptococcus gordonii. Recombinant bacteria expressing LTB were used to immunize BALB/c mice subcutaneously and intragastrically. The LTB monomer expressed on the streptococcal surface proved to be highly immunogenic, as LTB-specific immunoglobulin G (IgG) serum titers of 140,000 were induced after systemic immunization. Most significantly, these antibodies were capable of neutralizing the enterotoxin in a cell neutralization assay. Following mucosal delivery, antigen-specific IgA antibodies were found in feces and antigen-specific IgG antibodies were found in sera. Analysis of serum IgG subclasses showed a clear predominance of IgG1 when recombinant bacteria were inoculated subcutaneously, while a prevalence of IgG2a was observed upon intragastric delivery, suggesting, in this case, the recruitment of a Th1 type of immune response.

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“…Such studies are being conducted in several laboratories (see e.g., Sanchez et al, 1990;Nashar et al, 1993), including our own.…”

Section: Adjuvant Activity Of Lt and Ct: Structure-based Vaccine Designmentioning

confidence: 99%

Protein crystallography and infectious diseases

et al. 1994

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The current rapid growth in the number of known 3-dimensional protein structures is producing a database of structures that is increasingly useful as a starting point for the development of new medically relevant molecules such as drugs, therapeutic proteins, and vaccines. This development is beautifully illustrated in the recent book, Protein structure: New approaches to disease and therapy (Perutz, 1992). There is a great and growing promise for the design of molecules for the treatment or prevention of a wide variety of diseases, an endeavor made possible by the insights derived from the structure and function of crucial proteins from pathogenic organisms and from man.We present here 2 illustrations of structure-based drug design. The first is the prospect of developing antitrypanosoma1 drugs based on crystallographic, ligand-binding, and molecular modeling studies of glycolytic glycosomal enzymes from Trypanosomatidae. These unicellular organisms are responsible for several tropical diseases, including African and American trypanosomiases, as well as various forms of leishmaniasis. Because the target enzymes are also present in the human host, this project is a pioneering study in selective design. The second illustrative case is the prospect of designing anti-cholera drugs based on detailed analysis of the structure of cholera toxin and the closely related Escherichia coli heat-labile enterotoxin. Such potential drugs can be targeted either at inhibiting the toxin's receptor binding site or at blocking the toxin's intracellular catalytic activity.Study of the Vibrio cholerae and E. coli toxins serves at the same time as an example of a general approach to structure-based vaccine design. These toxins exhibit a remarkable ability to stimulate the mucosal immune system, and early results have suggested that this property can be maintained by engineered fusion proteins based on the native toxin structure. The challenge is thus to incorporate selected epitopes from foreign pathogens into the native framework of the toxin such that crucial features of both the epitope and the toxin are maintained.That is, the modified toxin must continue to evoke a strong mucosal immune response, and this response must be directed against an epitope conformation characteristic of the original pathogen.

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Recombinant cholera toxin B subunit and gene fusion proteins for oral vaccination

Cited by 48 publications

References 15 publications

Heat-Stable Enterotoxin of EnterotoxigenicEscherichia colias a Vaccine Target

Heat-Stable Enterotoxin of EnterotoxigenicEscherichia colias a Vaccine Target

Immunogenicity of the B Monomer ofEscherichia coliHeat-Labile Toxin Expressed on the Surface ofStreptococcus gordonii

Protein crystallography and infectious diseases

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