Safety and Immunogenicity of a Single Oral Dose of Recombinant Double Mutant Heat-Labile Toxin Derived from Enterotoxigenic Escherichia coli

El-Kamary, Samer S.; Cohen, Mitchell B.; Bourgeois, A. Louis; Verg, Lillian Van De; Bauers, Nicole; Reymann, Mardi; Pasetti, Marcela F.; Chen, Wilbur H.

doi:10.1128/cvi.00464-13

Cited by 54 publications

(39 citation statements)

References 31 publications

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“…Meanwhile, the 10 10 -CFU dosage appeared to demonstrate a trend for lower responses. Although this conclusion is limited by the small sample sizes, we have observed trends for lower immune responses with a high dosage (100 g) of orally administered nonreactogenic mutant LT (23). Similar trends for lower immune responses with high dosages of orally administered LT-based adjuvant have also been reported (24,25).…”

Section: Discussionsupporting

confidence: 63%

Safety and Immunogenicity of Escalating Dosages of a Single Oral Administration of Peru-15 pCTB, a Candidate Live, Attenuated Vaccine against Enterotoxigenic Escherichia coli and Vibrio cholerae

Chen

Garza

Choquette

et al. 2014

Clin. Vaccine Immunol.

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c Enterotoxigenic Escherichia coli (ETEC) organisms are a leading cause of infectious diarrhea in developing countries. A live, attenuated cholera strain that expresses high levels of the nontoxic B subunit of cholera toxin, which might also serve as an ETEC protective antigen, was evaluated for safety, excretion, and immunogenicity in healthy volunteers. We enrolled four inpatient dose-escalation cohorts of 15 to 16 eligible subjects to randomly (3:1) receive a single oral dose of vaccine or placebo (buffer alone), evaluating 1 ؋10 7 , 1 ؋10 8 , 1 ؋10 9 , and 1 ؋10 10 CFU of the vaccine. The vaccine was well tolerated, although some subjects experienced moderate diarrhea. The serum Inaba vibriocidal antibody response appeared to display a dose-response relationship with increasing dosages of vaccine, plateauing at the 10 9 -CFU dosage. The serum antitoxin (cholera toxin and heat-labile enterotoxin) antibody seroconversion rate (4-fold increase over baseline) also appeared to display a dose-response relationship. The vaccine strain was excreted in stool cultures, displaying a dose-response relationship. A single oral dose of Peru-15 pCTB at dosages up to 1 ؋10 10 CFU was safe and immunogenic in this first-in-human trial. These encouraging data support the ongoing clinical development of this candidate combined cholera and ETEC vaccine. (This study has been registered at ClinicalTrials.gov under registration no. NCT00654108.) O ne of the most important etiologic agents causing diarrhea among travelers from industrialized countries who visit developing countries is the mucosally noninvasive bacterial pathogen enterotoxigenic Escherichia coli (ETEC) (1-3). ETEC infections are also a leading cause of serious diarrheal illness and death in infants and young children in developing countries (4). Cumulatively, ETEC is estimated to cause ϳ600 million total cases of diarrhea worldwide annually, including ϳ280 million cases and Ͼ400,000 deaths in children Ͻ5 years of age (5).After the ingestion of contaminated food or water, ETEC organisms colonize the upper intestinal tract by a variety of antigenically distinct colonization factors (6). Once an infection is established, the bacteria secrete either a heat-labile toxin (LT), heat-stable toxin (ST), or both. ETEC strains are antigenically diverse, and the existence of many different O:H serotypes, multiple fimbrial colonization factors, and three different enterotoxin phenotypes (LT only, ST only, and LT plus ST) (7) have complicated vaccine development.However, LT is an oligomeric protein that is structurally, functionally, and antigenically similar to the cholera toxin (CT) of Vibrio cholerae and consists of a single enzymatically active subunit (LTA) and a pentameric complex of five identical receptor binding subunits (LTB) similar to the corresponding cholera toxin subunits (CTA and CTB, respectively). Although LT and CT have many features in common, they are clearly distinct molecules with biochemical and immunologic differences that make them unique (8). However, sev...

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Section: Discussionsupporting

confidence: 63%

Safety and Immunogenicity of Escalating Dosages of a Single Oral Administration of Peru-15 pCTB, a Candidate Live, Attenuated Vaccine against Enterotoxigenic Escherichia coli and Vibrio cholerae

Chen

Garza

Choquette

et al. 2014

Clin. Vaccine Immunol.

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“…Double-mutant LT (dmLT), with more than a 100-fold reduced enterotoxicity compared with native LT, was recently developed (4) and shown to enhance immune responses to various vaccines in animal models (4)(5)(6)(7)(8). Furthermore, dmLT was also shown to be safe and adjuvant-active when tested alone or together with an enteric vaccine in humans via the oral route (9,10). Recently, a similar but more easily produced nontoxic derivative of CT, multiple-mutated CT (mmCT), has also been generated and found to have strong adjuvant effects on mucosal B and T cell immune responses in animal studies (M. Lebens, S. Källgård, M. Terrinoni, S. Karlsson, M. Larena, T. Hedberg, E. Nygren, M. Blomquist, M. Löfstrand, J. Holmgren, manuscript in preparation).…”

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confidence: 99%

Cholera Toxin, and the Related Nontoxic Adjuvants mmCT and dmLT, Promote Human Th17 Responses via Cyclic AMP–Protein Kinase A and Inflammasome-Dependent IL-1 Signaling

Larena

Holmgren

Lebens

et al. 2015

The Journal of Immunology

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We have examined the molecular pathways involved in the adjuvant action of cholera toxin (CT) and two novel nontoxic molecules, multiple-mutated CT (mmCT) and double-mutant heat-labile toxin (dmLT) on human T cell responses. Human PBMCs or isolated monocytes were stimulated in vitro with CT, mmCT, or dmLT plus a polyclonal stimulus (staphylococcal enterotoxin B) or specific bacterial Ags, and effects on expression of cytokines and signaling molecules were determined. CT, mmCT, and dmLT strongly enhanced IL-17A and to a lesser extent IL-13 responses, but had little effect on IFN-γ production or cell proliferation. Intracellular cytokine staining revealed that the enhanced IL-17A production was largely confined to CD4+ T cells and coculture experiments showed that the IL-17A promotion was effectively induced by adjuvant-treated monocytes. Relative to CT, mmCT and dmLT induced at least 100-fold lower levels of cAMP, yet this cAMP was enough and essential for the promotion of Th17 responses. Thus, inhibition of cAMP-dependent protein kinase A was abolished, and stimulation with a cAMP analog mimicked the adjuvant effect. Furthermore, CT, mmCT, and dmLT induced IL-1β production and caspase-1 activation in monocytes, which was associated with increased expression of key proinflammatory and inflammasome-related genes, including NLRP1, NLRP3, and NLRC4. Inflammasome inhibition with a specific caspase-1 inhibitor, or blocking of IL-1 signaling by IL-1 receptor antagonist, abrogated the Th17-promoting effect. We conclude that CT, mmCT, and dmLT promote human Th17 responses via cAMP-dependent protein kinase A and caspase-1/inflammasome–dependent IL-1 signaling.

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“…After single administration of doses containing 10, 25, 50 or 100 mg of dmLT, diarrhea cases were not reported, and the formulation was well tolerated. 102 Systemic and mucosal humoral immune responses against LT were detected, particularly in the group receiving the 50 mg dose. Thus, dmLT is a suitable candidate for inclusion in multiple-antigen formulations or as an adjuvant.…”

Section: Double Mutant Ltmentioning

confidence: 97%

Vaccines for viral and bacterial pathogens causing acute gastroenteritis: Part II: Vaccines forShigella,Salmonella,enterotoxigenicE. coli(ETEC) enterohemorragicE. coli(EHEC) andCampylobacter jejuni

O’Ryan

Vidal

Canto

et al. 2015

Human Vaccines & Immunotherapeutics

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Safety and Immunogenicity of a Single Oral Dose of Recombinant Double Mutant Heat-Labile Toxin Derived from Enterotoxigenic Escherichia coli

Cited by 54 publications

References 31 publications

Safety and Immunogenicity of Escalating Dosages of a Single Oral Administration of Peru-15 pCTB, a Candidate Live, Attenuated Vaccine against Enterotoxigenic Escherichia coli and Vibrio cholerae

Safety and Immunogenicity of Escalating Dosages of a Single Oral Administration of Peru-15 pCTB, a Candidate Live, Attenuated Vaccine against Enterotoxigenic Escherichia coli and Vibrio cholerae

Cholera Toxin, and the Related Nontoxic Adjuvants mmCT and dmLT, Promote Human Th17 Responses via Cyclic AMP–Protein Kinase A and Inflammasome-Dependent IL-1 Signaling

Vaccines for viral and bacterial pathogens causing acute gastroenteritis: Part II: Vaccines forShigella,Salmonella,enterotoxigenicE. coli(ETEC) enterohemorragicE. coli(EHEC) andCampylobacter jejuni

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