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Interrogation of a live-attenuated enterotoxigenic Escherichia coli vaccine highlights features unique to wild-type infection.

ABSTRACT: Enterotoxigenic Escherichia coli (ETEC) infections are a common cause of severe diarrheal illness in low- and middle-income countries. The live-attenuated ACE527 ETEC vaccine, adjuvanted with double mutant heat-labile toxin (dmLT), affords clear but partial protection against ETEC challenge in human volunteers. Comparatively, initial wild-type ETEC challenge completely protects against severe diarrhea on homologous re-challenge. To investigate determinants of protection, vaccine antigen content was compared to wild-type ETEC, and proteome microarrays were used to assess immune responses following vaccination and ETEC challenge. Although molecular interrogation of the vaccine confirmed expression of targeted canonical antigens, relative to wild-type ETEC, vaccine strains were deficient in production of flagellar antigens, immotile, and lacked production of the EtpA adhesin. Similarly, vaccination?±?dmLT elicited responses to targeted canonical antigens, but relative to wild-type challenge, vaccine responses to some potentially protective non-canonical antigens including EtpA and the YghJ metalloprotease were diminished or absent. These studies highlight important differences in vaccine and wild-type ETEC antigen content and call attention to distinct immunologic signatures that could inform investigation of correlates of protection, and guide vaccine antigen selection for these pathogens of global importance.

SUBMITTER: Chakraborty S

PROVIDER: S-EPMC6713706 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Interrogation of a live-attenuated enterotoxigenic <i>Escherichia coli</i> vaccine highlights features unique to wild-type infection.

Chakraborty Subhra S Randall Arlo A Vickers Tim J TJ Molina Doug D Harro Clayton D CD DeNearing Barbara B Brubaker Jessica J Sack David A DA Bourgeois A Louis AL Felgner Philip L PL Liang Xiaowu X Mani Sachin S Wenzel Heather H Townsend R Reid RR Gilmore Petra E PE Darsley Michael J MJ Rasko David A DA Fleckenstein James M JM

NPJ vaccines 20190828

Enterotoxigenic <i>Escherichia coli</i> (ETEC) infections are a common cause of severe diarrheal illness in low- and middle-income countries. The live-attenuated ACE527 ETEC vaccine, adjuvanted with double mutant heat-labile toxin (dmLT), affords clear but partial protection against ETEC challenge in human volunteers. Comparatively, initial wild-type ETEC challenge completely protects against severe diarrhea on homologous re-challenge. To investigate determinants of protection, vaccine antigen c ...[more]

PMID: 31482013

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Project description:BACKGROUND:There is no licensed vaccine against enterotoxigenic Escherichia coli (ETEC), a major cause of diarrhea-associated morbidity and mortality among infants and children in low-income countries and travelers. The results of this vaccination/challenge study demonstrate strong protection by an attenuated ETEC vaccine candidate, ACE527, when co-administered with a mucosal adjuvant, the double-mutant heat-labile toxin (dmLT) of ETEC. METHODS:Sixty healthy adults participated in a randomized, placebo-controlled, double-blind study with three doses of lyophilized ACE527 (?3?×?109 of each strain per dose) administered orally with or without dmLT adjuvant (25?µg/dose). Six months later, 36 of these volunteers and a control group of 21 unvaccinated volunteers were challenged with virulent ETEC strain H10407. The primary outcome was severe diarrhea, defined as passing >800?g of unformed stools during the inpatient period following challenge. FINDINGS:The vaccine was well tolerated and induced robust immune responses to key antigens. The protective efficacy (PE) against the primary outcome of severe diarrhea was 65.9% (95% confidence interval [CI] 5.4-87.7, p?=?0.003). Among subjects receiving the adjuvanted vaccine, the attack rate of severe diarrhea was 23.1, while in unimmunized controls it was 67.7%. The PE against diarrhea of any severity was 58.5% (95% CI 3.8- 82.1, p?=?0.016). There was a strong inverse correlation between shedding of the vaccine strain after either of the first two doses and absence of severe diarrhea upon challenge (RR?=?0.29, 95% CI 0.08-1.05, p?=?0.041). Challenge strain shedding was 10-fold lower in those receiving the adjuvant than in those receiving vaccine alone. The unadjuvanted vaccine was not protective (PE?=?23.1%). INTERPRETATION:The results of this study support further development of ACE527?+?dmLT as a vaccine for children in endemic countries and travelers. This is the first clinical demonstration that dmLT can contribute significantly to vaccine efficacy and may warrant testing with other oral vaccines. (ClinicalTrials.gov registration: NCT01739231).

Project description:Enterotoxigenic Escherichia coli (ETEC) is an important cause of diarrhea in children in low- and middle-income countries (LMICs). However, large-scale pathogen burden studies in children have identified ETEC in the guts of both symptomatic patients and controls. The factors that influence this balance are poorly understood, but it is postulated that the gut microbiome may play a role in either resistance or progression to disease. In this study, we profiled the microbiomes of children and adults from Bangladesh who were asymptomatically or symptomatically infected with ETEC. Symptomatic patients had significantly higher numbers of sequenced reads mapping to both E. coli and two ETEC toxins, suggesting higher bacterial burden. They were also significantly more likely to be coinfected with enteroaggregative E. coli (EAEC) and had higher proportions of other Gammaproteobacteria, including Klebsiella, Salmonella, and Haemophilus. Colonization with ETEC was also associated with increased prevalence of antimicrobial resistance (AMR) genes, most notably those of the β-lactamase class. Taxonomic profiles were distinctly different between all groups in both species richness and composition, although the direction of these changes was different in adults and children. As seen previously, children with high E. coli burdens also had higher proportions of Streptococcus spp., while healthy children were more heavily colonized by Bifidobacterium spp. Our study provides insight into the microbiome changes that occur upon infection with ETEC in an endemic setting and provides rationale for future studies investigating how the microbiome may protect or predispose individuals to symptomatic infections with gastrointestinal pathogens. IMPORTANCE Enterotoxigenic Escherichia coli (ETEC) is an important cause of diarrhea in children in low- and middle-income countries. However, these bacteria are often identified in both patients and healthy controls. We do not yet understand why only some people get sick, but it has been suggested that the gut microbiome might play a role. In this study, we used metagenomic sequencing to profile the gut microbiomes of individuals in Bangladesh, with or without a symptomatic ETEC infection. In general, individuals with high levels of ETEC also harbored other pathogenic E. coli strains, higher proportions of Gammaproteobacteria such as Salmonella and Klebsiella, and a higher burden of antimicrobial resistance genes in their guts. Healthy children, in contrast, had higher levels of bifidobacteria. These data confirm that the composition of the gut microbiome is different between symptomatic and asymptomatic people and provides important preliminary information on the impact of the gut microbiome in intestinal infections.

Dataset Information

Interrogation of a live-attenuated enterotoxigenic Escherichia coli vaccine highlights features unique to wild-type infection.

Publications

Interrogation of a live-attenuated enterotoxigenic <i>Escherichia coli</i> vaccine highlights features unique to wild-type infection.

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