Oral delivery of Hyperimmune bovine serum antibodies against CS6-expressing enterotoxigenic Escherichia coli as a prophylactic against diarrhea.

BACKGROUND: . Oral administration of bovine antibodies active against enterotoxigenic Escherichia coli (ETEC) have demonstrated safety and efficacy against diarrhea in human challenge trials. The efficacy of bovine serum immunoglobulins (BSIgG) against recombinant colonization factor CS6 or whole cell ETEC strain B7A was assessed against challenge with the CS6-expressing B7A. METHODS: . This was a randomized, double-blind, placebo-controlled trial in which healthy adults received oral hyperimmune BSIgG anti-CS6, anti-B7A whole cell killed or non-hyperimmune BSIgG (placebo) in a 1:1:1 ratio then challenged with ETEC B7A. Two days pre-challenge, volunteers began a thrice daily, seven day course of immunoprophylaxis. On day 3, subjects received 1 × 1010 CFUs of B7A. Subjects were observed for safety and the primary endpoint of moderate-severe diarrhea (MSD). RESULTS: . A total of 59 volunteers received product and underwent ETEC challenge. The BSIgG products were well-tolerated across all subjects. Upon challenge, 14/20 (70%) placebo recipients developed MSD, compared to 12/19 (63%; p = .74) receiving anti-CS6 BSIgG and 7/20 (35%; p = .06) receiving anti-B7A BSIgG. Immune responses to the ETEC infection were modest across all groups. CONCLUSIONS: . Bovine-derived serum antibodies appear safe and well tolerated. Antibodies derived from cattle immunized with whole cell B7A provided 50% protection against MSD following B7A challenge; however, no protection was observed in subjects receiving serum antibodies targeting CS6. The lack of observed efficacy in this group may be due to low CS6 surface expression on B7A, the high dose challenge inoculum and/or the use of serum derived antibodies versus colostrum-derived antibodies.

Epidemiology of inflammatory bowel disease among participants of the Millennium Cohort: incidence, deployment-related risk factors, and antecedent episodes of infectious gastroenteritis.

BACKGROUND: Crohn's disease (CD) and ulcerative colitis (UC) are two pathotypes of inflammatory bowel disease (IBD) with unique pathology, risk factors and significant morbidity. AIM: To estimate incidence and identify IBD risk factors in a US military population, a healthy subset of the US population, using information from the Millennium Cohort Study. METHODS: Incident IBD was identified from medical encounters from 2001 to 2009 or by self-report. Our primary risk factor of interest, infectious gastroenteritis, was identified from medical encounters and self-reported post-deployment health assessments. Other potential risk factors were assessed using self-reported survey responses and military personnel files. Hazard ratios were estimated using Cox proportional hazards analysis. RESULTS: We estimated 23.2 and 21.9 diagnoses per 100 000 person-years, respectively, for CD and UC. For CD, significant risk factors included [adjusted hazard ratio (aHR), 95% confidence interval]: current smoking (aHR: 2.7, 1.4-5.1), two life stressors (aHR: 2.8, 1.4-5.6) and prior irritable bowel syndrome (aHR: 4.7, 1.5-15.2). There was no significant association with prior infectious gastroenteritis. There was an apparent dose-response relationship between UC risk and an increasing number of life stressors. In addition, antecedent infectious gastroenteritis was associated with almost a three-fold increase in UC risk (aHR: 2.9, 1.4-6.0). Moderate alcohol consumption (aHR: 0.4, 0.2-0.6) was associated with lower UC risk. CONCLUSIONS: Stressful conditions and the high risk of infectious gastroenteritis in deployment operations may play a role in the development of IBD in military populations. However, observed differences in risk factors for UC and CD warrant further investigation.

Serologic microbial associated markers can predict Crohn's disease behaviour years before disease diagnosis.

BACKGROUND: Patients with Crohn's disease (CD) have serologic responses to various microbial antigens. Serologic markers are associated with aggressive forms of disease and can be detected before onset of symptoms. Their utility in pre-clinical disease or prediction of complicated disease course before diagnosis is unclear. AIM: To evaluate the pattern of serologic anti-microbial antibodies long prior to diagnosis and the subsequent risk of complicated Crohn's disease at diagnosis. METHODS: Sera from 100 US military personnel with Crohn's disease were obtained from the Department of Defense Serum Repository. For each patient, four samples were obtained at different time points before and around diagnosis, and were tested for 6 microbiota-directed antibodies (ASCA-IgA, ASCA-IgG, anti-OmpC, anti-CBir1, anti-A4-Fla2 and anti-FlaX). Associations between the presence and accumulation of Crohn's disease anti-microbial antibodies before diagnosis and with the later development of complications were evaluated. RESULTS: Overall, 65 patients were positive for at least one Crohn's disease associated anti-microbial antibody in the earliest available sample, at a median of 6 years before Crohn's disease diagnosis (interquartile range, 5.6-8.2). The number of positive anti-microbial antibodies increased up to the time of Crohn's disease diagnosis. Complicated disease developed around the time of diagnosis in 24 patients. The proportion of positive antimicrobial antibodies before diagnosis was higher in patients with complicated vs. noncomplicated Crohn's disease. There was an inverse relationship between the time to first complication and the magnitude of serologic response before diagnosis. CONCLUSION: The presence and accumulation of circulating anti-microbial antibodies years before Crohn's disease diagnosis was associated with complicated Crohn's disease at or shortly after diagnosis.

The Shigella human challenge model.

Shigella is an important bacterial cause of infectious diarrhoea globally. The Shigella human challenge model has been used since 1946 for a variety of objectives including understanding disease pathogenesis, human immune responses and allowing for an early assessment of vaccine efficacy. A systematic review of the literature regarding experimental shigellosis in human subjects was conducted. Summative estimates were calculated by strain and dose. While a total of 19 studies evaluating nine strains at doses ranging from 10 to 1 × 1010 colony-forming units were identified, most studies utilized the S. sonnei strain 53G and the S. flexneri strain 2457T. Inoculum solution and pre-inoculation buffering has varied over time although diarrhoea attack rates do not appear to increase above 75-80%, and dysentery rates remain fairly constant, highlighting the need for additional dose-ranging studies. Expansion of the model to include additional strains from different serotypes will elucidate serotype and strain-specific outcome variability.

A systematic review of ETEC epidemiology focusing on colonization factor and toxin expression.

INTRODUCTION: Vaccine development for enterotoxigenic Escherichia coli (ETEC) is dependent on in-depth understanding of toxin and colonization factor (CF) distribution. We sought to describe ETEC epidemiology across regions and populations, focusing on CF and toxin prevalence. METHODS: We conducted a systematic review of the published literature, including studies reporting data on ETEC CF and toxin distributions among those with ETEC infection. Point estimates and confidence intervals were calculated using random effects models. RESULTS: Data on 17,205 ETEC isolates were abstracted from 136 included studies. Approximately half of the studies (49%) involved endemic populations, and an additional 17% involved only travel populations. Globally, 60% of isolates expressed LT either alone (27%) or in combination with ST (33%). CFA/I-expressing strains were common in all regions (17%), as were ETEC expressing CFA/II (9%) and IV (18%). Marked variation in toxins and CFs across regions and populations was observed. DISCUSSION/CONCLUSIONS: These results demonstrate the relative importance of specific CFs in achieving target product profiles for a future ETEC vaccine. However, heterogeneity across time, population, and region, confounded by variability in CF and toxin detection methodologies, obfuscates rational estimates for valency requirements.

Caught in the act: in vivo development of macrolide resistance to Campylobacter jejuni infection.

We report the first instance of macrolide resistance developing in vivo following appropriate antibiotic use in a healthy volunteer as a part of a controlled human infection with Campylobacter jejuni. In vivo development of macrolide resistance may be an important contributor to antibiotic resistance in C. jejuni.

Case series study of traveler's diarrhea in U.S. military personnel at Incirlik Air Base, Turkey.

Military personnel with traveler's diarrhea (n=202) while deployed to Incirlik Air Base, Turkey, from June to September 2002 were evaluated for pathogen-specific immune responses. Serologic and fecal immunoglobulin A (IgA) titers to enterotoxigenic Escherichia coli antigens (CS6, CS3, and LT) were quite low. In contrast, subjects with Campylobacter infections had high serologic and fecal IgA responses.