Evaluation of the safety and immunogenicity of the oral inactivated multivalent enterotoxigenic Escherichia coli vaccine ETVAX in Bangladeshi adults in a double-blind, randomized, placebo-controlled Phase I trial using electrochemiluminescence and ELISA assays for immunogenicity analyses

Akhtar, Marjahan; Chowdhury, Mohiul I.; Bhuiyan, Taufiqur Rahman; Kaim, Joanna; Ahmed, Tasnuva; Rafique, Tanzeem Ahmed; Khan, Arifuzzaman; Rahman, Sadia Isfat Ara; Khanam, Farhana; Begum, Yasmin; Sharif, Mir Z.; Islam, Laila N.; Carlin, Nils; Maier, Nicole; Fix, Alan; Wierzba, Thomas F.; Walker, Richard I.; Bourgeois, A. Louis; Svennerholm, Ann Mari; Qadri, Firdausi; Lundgren, Anna

doi:10.1016/j.vaccine.2018.11.040

Cited by 50 publications

(55 citation statements)

References 46 publications

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“…It is conceivable that the inclusion of LTB or CTB/LTB hybrids with broader binding specificities could make vaccines more effective to combat several types of enterotoxigenic infections. This strategy is currently probed in clinical trials with the 2 nd generation oral ETEC vaccine [34,35], which includes a CTB/LTB chimera as well as a double-mutated LT holotoxin (dmLT) [36]. The work presented here may further aid the development of improved cholera and ETEC vaccines.…”

Section: Discussionmentioning

confidence: 99%

Specificity of <em>Escherichia coli</em> Heat-Labile Enterotoxin Investigated by Single-Site Mutagenesis

Heggelund¹,

Heim²,

Bajc³

et al. 2018

Preprint

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Diarrhoea caused by enterotoxigenic Escherichia coli is one of the leading causes of mortality in children under five years of age and is a great burden on developing countries. The major virulence factor of the bacterium is the heat-labile enterotoxin (LT), a close homologue of the cholera toxin. The toxins bind to carbohydrate receptors in the gastrointestinal tract, leading to toxin uptake and, ultimately, to severe diarrhoea. Previously, LT from human- and porcine-infecting ETEC (hLT and pLT, respectively) were shown to have different carbohydrate-binding specificities, in particular with respect to N-acetyllactosamine-terminating glycosphingolipids. Here, we probed eleven single-residue variants of the heat-labile enterotoxin with surface plasmon resonance spectroscopy and compared the data to the parent toxins. In addition we present a 1.45 Å crystal structure of pLTB in complex with branched Lacto-N-neohexaose (Galb4GlcNAcb6[Galb4GlcNAcb3]Galb4Glc). The largest difference in binding specificity is caused by mutation of residue 94, which links the primary and secondary binding sites of the toxins. Residue 95 (and to a smaller extent also residues 7 and 18) also contribute, whereas residue 4 shows no effect on monovalent binding of the ligand and may rather be important for multivalent binding, enhancing avidity.

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Section: Discussionmentioning

confidence: 99%

Specificity of <em>Escherichia coli</em> Heat-Labile Enterotoxin Investigated by Single-Site Mutagenesis

Heggelund¹,

Heim²,

Bajc³

et al. 2018

Preprint

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“…We have identified these timepoints to be optimal for assessing circulating antibody-secreting cell or ALS responses after oral vaccination, with only minor differences in plasma IgA and IgG responses between day 5 and later timepoints after the second dose. 16,21,22 Immune responses were assessed by measuring vaccine-specific (ie, CFA/I, CS3, CS5, CS6, and LTB) IgA antibodies in ALS specimens 16,18,23 and IgA antibody levels against the five vaccine antigens and IgG antibody concentrations against LTB in plasma. 16,23,24 See Online for appendix Peripheral blood mononuclear cells (PBMCs) and plasma were separated from the blood by density-gradient centrifugation on Ficoll-Isopaque.…”

Section: Methodsmentioning

confidence: 99%

“…For ALS preparations, 10⁷ PBMCs per mL were cultured for 48 h at 37°C with 5% CO₂; supernatants were collected and stored at −70°C. 16,18,22 To enable analysis of ALS responses to all primary vaccine antigens in the small sample volumes available from children, a highly sensitive electrochemi luminescence assay was established based on Meso Scale Discovery (Rockville, MD, USA) technology. Electrochemiluminiscence and ELISA results were shown to be highly correlated in adults.…”

Section: Methodsmentioning

confidence: 99%

“…First, we assessed the safety and immunogenicity of ETVAX in adults aged 18-45 years in Bangladesh. 18 The results in adults indicated that ETVAX was safe and induced ALS responses against all five primary vaccine antigens in 100% of vaccinees and strong plasma immune responses in 60-100%. 18 On the basis of the safety data in adults, we proceeded to assess the vaccine in children, with the primary objective to establish the largest tolerated dose of ETVAX, with or without dmLT.…”

Section: Introductionmentioning

confidence: 97%

“…18 The results in adults indicated that ETVAX was safe and induced ALS responses against all five primary vaccine antigens in 100% of vaccinees and strong plasma immune responses in 60-100%. 18 On the basis of the safety data in adults, we proceeded to assess the vaccine in children, with the primary objective to establish the largest tolerated dose of ETVAX, with or without dmLT. A secondary objective was to assess the potential of the vaccine to induce mucosal and systemic immune responses against the five primary vaccine antigens.…”

Section: Introductionmentioning

confidence: 97%

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Safety and immunogenicity of the oral, inactivated, enterotoxigenic Escherichia coli vaccine ETVAX in Bangladeshi children and infants: a double-blind, randomised, placebo-controlled phase 1/2 trial

Qadri

Akhtar

Bhuiyan

et al. 2020

The Lancet Infectious Diseases

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Background Enterotoxigenic Escherichia coli causes diarrhoea, leading to substantial mortality and morbidity in children, but no specific vaccine exists. This trial tested an oral, inactivated, enterotoxigenic E coli vaccine (ETVAX), which has been previously shown to be safe and highly immuongenic in Swedish and Bangladeshi adults. We tested the safety and immunogenicity of ETVAX, consisting of four E coli strains overexpressing the most prevalent colonisation factors (CFA/I, CS3, CS5, and CS6) and a toxoid (LCTBA) administered with or without a double-mutant heat-labile enterotoxin (dmLT) as an adjuvant, in Bangladeshi children. Methods We did a randomised, double-blind, placebo-controlled, dose-escalation, age-descending, phase 1/2 trial in Dhaka, Bangladesh. Healthy children in one of three age groups (24-59 months, 12-23 months, and 6-11 months) were eligible. Children were randomly assigned with block randomisation to receive either ETVAX, with or without dmLT, or placebo. ETVAX (half [5•5 × 10¹⁰ cells], quarter [2•5 × 10¹⁰ cells], or eighth [1•25 × 10¹⁰ cells] adult dose), with or without dmLT adjuvant (2•5 µg, 5•0 µg, or 10•0 µg), or placebo were administered orally in two doses 2 weeks apart. Investigators and participants were masked to treatment allocation. The primary endpoint was safety and tolerability, assessed in all children who received at least one dose of vaccine. Antibody responses to vaccine antigens, defined as at least a two-times increase in antibody levels between baseline and post-immunisation, were assessed as secondary endpoints. This trial is registered with ClinicalTrials.gov, NCT02531802.

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Recent Progress on Enterotoxigenic E. coli (ETEC) and Antibiotic Resistance in Pathogenic E. coli

Joffré

Zurita

Toledo

et al. 2023

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Evaluation of the safety and immunogenicity of the oral inactivated multivalent enterotoxigenic Escherichia coli vaccine ETVAX in Bangladeshi adults in a double-blind, randomized, placebo-controlled Phase I trial using electrochemiluminescence and ELISA assays for immunogenicity analyses

Cited by 50 publications

References 46 publications

Specificity of <em>Escherichia coli</em> Heat-Labile Enterotoxin Investigated by Single-Site Mutagenesis

Specificity of <em>Escherichia coli</em> Heat-Labile Enterotoxin Investigated by Single-Site Mutagenesis

Safety and immunogenicity of the oral, inactivated, enterotoxigenic Escherichia coli vaccine ETVAX in Bangladeshi children and infants: a double-blind, randomised, placebo-controlled phase 1/2 trial

Recent Progress on Enterotoxigenic E. coli (ETEC) and Antibiotic Resistance in Pathogenic E. coli

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