Dataset Information

Safety and immunogenicity of ETVAX®, an oral inactivated vaccine against enterotoxigenic Escherichia coli diarrhoea: a double-blinded, randomized, placebo-controlled trial amongst Finnish travellers to Benin, West Africa.

ABSTRACT:

Background

No licensed human vaccines are available against enterotoxigenic Escherichia coli (ETEC), a major diarrhoeal pathogen affecting children in low- and middle-income countries and foreign travellers alike. ETVAX®, a multivalent oral whole-cell vaccine containing four inactivated ETEC strains and the heat-labile enterotoxin B subunit (LTB), has proved promising in Phase 1 and Phase 1/ 2 studies.

Methods

We conducted a Phase 2b double-blinded, randomized, placebo-controlled trial amongst Finnish travellers to Benin, West Africa. This report presents study design and safety and immunogenicity data. Volunteers aged 18-65 years were randomized 1:1 to receive ETVAX® or placebo. They visited Benin for 12 days, provided stool and blood samples and completed adverse event (AE) forms. IgA and IgG antibodies to LTB and O78 lipopolysaccharide (LPS) were measured by electrochemiluminescence.

Results

The AEs did not differ significantly between vaccine (n = 374) and placebo (n = 375) recipients. Of the solicited AEs, loose stools/diarrhoea (26.7/25.9%) and stomach ache (23.0/20.0%) were reported most commonly. Of all possibly/probably vaccine-related AEs, the most frequent were gastrointestinal symptoms (54.0/48.8%) and nervous system disorders (20.3/25.1%). Serious AEs were recorded for 4.3/5.6%, all unlikely to be vaccine related. Amongst the ETVAX® recipients, LTB-specific IgA antibodies increased 22-fold. For the 370/372 vaccine/placebo recipients, the frequency of ≥2-fold increases against LTB was 81/2.4%, and against O78 LPS 69/2.7%. The majority of ETVAX® recipients (93%) responded to either LTB or O78.

Conclusions

This Phase 2b trial is the largest on ETVAX® undertaken amongst travellers to date. ETVAX® showed an excellent safety profile and proved strongly immunogenic, which encourages the further development of this vaccine.

SUBMITTER: Kantele A

PROVIDER: S-EPMC10658657 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Publications

Safety and immunogenicity of ETVAX®, an oral inactivated vaccine against enterotoxigenic Escherichia coli diarrhoea: a double-blinded, randomized, placebo-controlled trial amongst Finnish travellers to Benin, West Africa.

Kantele Anu A Riekkinen Marianna M Jokiranta T Sakari TS Pakkanen Sari H SH Pietilä Jukka-Pekka JP Patjas Anu A Eriksson Mari M Khawaja Tamim T Klemets Peter P Marttinen Kati K Siikamäki Heli H Lundgren Anna A Holmgren Jan J Lissmats Agneta A Carlin Nils N Svennerholm Ann-Mari AM

Journal of travel medicine 20231101 7

<h4>Background</h4>No licensed human vaccines are available against enterotoxigenic Escherichia coli (ETEC), a major diarrhoeal pathogen affecting children in low- and middle-income countries and foreign travellers alike. ETVAX®, a multivalent oral whole-cell vaccine containing four inactivated ETEC strains and the heat-labile enterotoxin B subunit (LTB), has proved promising in Phase 1 and Phase 1/ 2 studies.<h4>Methods</h4>We conducted a Phase 2b double-blinded, randomized, placebo-controlled ...[more]

PMID: 37099803

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Project description:BackgroundAcute gastroenteritis (AGE) is a major medical condition for travellers worldwide, particularly travellers to low- and middle-income countries. Norovirus (NoV) is the most common cause of viral AGE in older children and adults, but data on prevalence and impact amongst travellers is limited.MethodsProspective, multi-site, observational cohort study conducted 2015-2017, amongst adult international travellers from the US and Europe to areas of moderate to high risk of travel-acquired AGE. Participants provided self-collected pre-travel stool samples and self-reported AGE symptoms whilst travelling. Post-travel stool samples were requested from symptomatic subjects and a sample of asymptomatic travellers within 14 days of return. Samples were tested for NoV by RT-qPCR, genotyped if positive and tested for other common enteric pathogens by Luminex xTAG GPP.ResultsOf the 1109 participants included, 437 (39.4%) developed AGE symptoms resulting in an overall AGE incidence of 24.7 per 100 person-weeks [95% confidence interval (CI): 22.4; 27.1]. In total, 20 NoV-positive AGE cases (5.2% of those tested) were identified at an incidence of 1.1 per 100 person-weeks (95% CI: 0.7; 1.7). NoV-positive samples belonged mostly to genogroup GII (18, 85.7%); None of the 13 samples sequenced belonged to genotype GII.4. Clinical severity of AGE was higher for NoV-positive than for NoV-negative cases (mean modified Vesikari Score 6.8 vs 4.9) with more cases classified as severe or moderate (25% vs 6.8%). In total, 80% of NoV-positive participants (vs 38.9% in NoV-negative) reported at least moderate impact on travel plans.ConclusionsAGE is a prevalent disease amongst travellers with a small proportion associated with NoV. Post-travel stool sample collection timing might have influenced the low number of NoV cases detected; however, NoV infections resulted in high clinical severity and impact on travel plans. These results may contribute to targeted vaccine development and the design of future studies on NoV epidemiology.

Project description:BackgroundEnterotoxigenic 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.MethodsWe 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.FindingsBetween Dec 7, 2015, and Jan 10, 2017, we screened 1500 children across the three age groups, of whom 430 were enrolled and randomly assigned to the different treatment groups (130 aged 24-59 months, 100 aged 12-23 months, and 200 aged 6-11 months). All participants received at least one dose of vaccine. No solicited adverse events occurred that were greater than moderate in severity, and most were mild. The most common solicited event was vomiting (ten [8%] of 130 patients aged 24-59 months, 13 [13%] of 100 aged 12-23 months, and 29 [15%] of 200 aged 6-11 months; mostly of mild severity), which appeared related to dose and age. The addition of dmLT did not modify the safety profile. Three serious adverse events occurred but they were not considered related to the study drug. Mucosal IgA antibody responses in lymphocyte secretions were detected against all primary vaccine antigens (CFA/I, CS3, CS5, CS6, and the LCTBA toxoid) in most participants in the two older age groups, whereas such responses to four of the five antigens were less frequent and of lower magnitude in infants aged 6-11 months than in older children. Faecal secretory IgA immune responses were recorded against all vaccine antigens in infants aged 6-11 months. 78 (56%) of 139 infants aged 6-11 months who were vaccinated developed mucosal responses against at least three of the vaccine antigens versus 14 (29%) of 49 of the infants given placebo. Addition of the adjuvant dmLT enhanced the magnitude, breadth, and kinetics (based on number of responders after the first dose of vaccine) of immune responses in infants.InterpretationThe encouraging safety and immunogenicity of ETVAX and benefit of dmLT adjuvant in young children support its further assessment for protective efficacy in children in enterotoxigenic E coli-endemic areas.FundingPATH (Bill & Melinda Gates Foundation and the UK's Department for International Development), the Swedish Research Council, and The Swedish Foundation for Strategic Research.

Project description:The safety and immunogenicity of the second generation oral enterotoxigenic Escherichia coli (ETEC) vaccine ETVAX, consisting of inactivated recombinant E. coli strains over-expressing the colonization factors (CFs) CFA/I, CS3, CS5 and CS6 and the heat labile toxoid LCTBA, were evaluated in Bangladeshi volunteers. To enable analysis of antibody responses against multiple vaccine antigens for subsequent use in small sample volumes from children, a sensitive electrochemiluminescence (ECL) assay for analysis of intestine-derived antibody-secreting cell responses using the antibodies in lymphocyte secretions (ALS) assay was established using Meso Scale Discovery technology. Three groups of Bangladeshi adults (n = 15 per group) received two oral doses of ETVAX with or without double mutant LT (dmLT) adjuvant or placebo in the initial part of a randomized, double-blind, placebo-controlled, age-descending, dose-escalation trial. CF- and LTB-specific ALS and plasma IgA responses were analyzed by ECL and/or ELISA. ETVAX was safe and well tolerated in the adults. Magnitudes of IgA ALS responses determined by ECL and ELISA correlated well (r = 0.85 to 0.98 for the five primary antigens, P < 0.001) and ECL was selected as the ALS readout method. ALS IgA responses against each of the primary antigens were detected in 87-100% of vaccinees after the first and in 100% after the second vaccine dose. Plasma IgA responses against different CFs and LTB were observed in 62-93% and 100% of vaccinees, respectively. No statistically significant adjuvant effect of dmLT on antibody responses to any antigen was detected, but the overall antigenic breadth of the plasma IgA response tended to favor the adjuvanted vaccine when responses to 4 or more or 5 vaccine antigens were considered. Responses in placebo recipients were infrequent and mainly detected against single antigens. The promising results in adults supported testing ETVAX in descending age groups of children. ClinicalTrials.gov Identifier: NCT02531802.

Project description:IntroductionTravellers' diarrhoea (TD) continues to be the most common travel-related medical event in international travellers. Updated incidence and risk factor data will improve pre-travel medical advice for travellers from high-income countries (HICs), providing an opportunity for disease prevention and appropriate disease management.MethodsA systematic search for cohort studies of TD incidence published between 1 January 1997 and 2 March 2023 was performed using Ovid Medline, SCOPUS and Google Scholar databases. Study quality was assessed with a modified Newcastle-Ottawa Scale (NOS). We extracted incidence data for adults travelling less than 100 days from HIC and available risk factor data. The overall random-effects pooled incidence and the corresponding 95% confidence intervals (95% CI) were estimated. Heterogeneity was assessed using the I2 statistic, tau and the 95% prediction intervals. Subgroup analyses were conducted to identify the sources of heterogeneity. Risk factor studies were reviewed qualitatively and described.ResultsTen studies were included in the meta-analysis, containing 8478 participants. Two of the studies measured as high quality and eight as good quality as assessed by the modified NOS. The TD incidence was 36.1% (95% CI 24-41%; I2 94%), with a prediction interval ranging from 20.3 to 55.8%. The pooled incidence of mild, moderate and severe TD was 23.6, 8.1 and 2.9%, respectively. Subgroup analysis showed that the incidence increased with increasing average data collection period. Risk factors for TD in travellers from HIC identified include younger age, longer travel periods, low and middle-income destinations, travelling for tourism, backpacking travel styles and pre-travel health status.ConclusionIt is estimated that between 20 and 56% of international travellers can expect to develop TD in travel of under 100 days. While most cases are mild, ~3% of all travellers will experience a disease that prevents usual activities or requires medical attention.

Project description:Backgroundtravellers' diarrhoea (TD) is frequently reported with incidence up to 40% in high-risk destinations. Previous studies showed that the number of loose stools alone is inadequate to holistically predict the severity of TD. To improve the prediction of prognosis and to optimize treatments, a simple risk-based clinical severity classification has been developed.Methodspooled baseline data of signs and symptoms and number of loose stools from 1098 subjects enrolled in two double-blind Phase 3 trials of rifamycin-SV were analyzed with correlation, multiple correspondence analyses, prognostic factor criteria, and Contal and O'Quigley method to generate a TD severity classification (mild, moderate and severe). The relative importance of this classification on resolution of TD was assessed by Cox proportional model hazard model on the time to last unformed stool (TLUS).Resultsthe analysis showed that TLUS were longer for the severe [hazard ratio (HR) 0.24; P < 0.001; n = 173] and moderate (HR 0.54; P = 0.0272; n = 912) vs mild. Additionally, when the treatment assigned in the studies was investigated in the severity classification, the results yielded that rifamycin-SV significantly shortened TLUS vs placebo for all subjects (HR 1.9; P = 0.0006), severe (HR 5.9; P = 0.0232) and moderate (HR 1.7; P = 0.0078) groups and was as equally efficacious as ciprofloxacin for all subjects, moderate and severe groups (HRs: 0.962, 0.9, 1.2; all P = NS, respectively). When reassessed by this classification, rifamycin-SV showed consistent efficacy with the Phase 3 studies.Conclusionsthis newly developed TD clinical severity classification demonstrated strong prognostic value and clinical utility by combining patients' multiple signs and symptoms of enteric infection and number of loose stools to provide a holistic assessment of TD. By expanding on the current classification by incorporating patient reported outcomes in addition to TLUS, a classification like the one developed, may help optimize patient selection for future clinical studies.

Dataset Information

Safety and immunogenicity of ETVAX®, an oral inactivated vaccine against enterotoxigenic Escherichia coli diarrhoea: a double-blinded, randomized, placebo-controlled trial amongst Finnish travellers to Benin, West Africa.

Background

Methods

Results

Conclusions

Publications

Safety and immunogenicity of ETVAX®, an oral inactivated vaccine against enterotoxigenic Escherichia coli diarrhoea: a double-blinded, randomized, placebo-controlled trial amongst Finnish travellers to Benin, West Africa.

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