Refinement of a Human Challenge Model for Evaluation of Enterotoxigenic Escherichia coli Vaccines

Abstract

Enterotoxigenic Escherichia coli (ETEC) is a leading bacterial cause of infectious diarrhea in infants and adults living in developing countries and accounts for approximately 30% of traveler's diarrhea in visitors to these regions (6, 21, 23-26, 28, 29, 35). ETEC strains vary in their pathogenicity as a result of differences in the expression of heat-labile toxin (LT), heatstable toxin (ST), and several colonization factors (CFAs) that are associated with attachment and colonization in the gut (23,31). For more than 40 years, human challenge models have been the mainstay for the clinical evaluation of ETEC pathogenesis and immunology (7,15) and for the assessment of the therapeutic and protective efficacy of antibiotics (2), probiotics (4), and candidate vaccines (18,19). The recent availability of new resources for ETEC vaccine development has renewed interest in ETEC challenge models. A model with a reliably high attack rate (AR) could provide a vehicle for the evaluation and screening of vaccine efficacy before expensive, longterm field trials are conducted in areas where ETEC is endemic or among at-risk travelers.

Development and Accuracy of Quantitative Real-Time Polymerase Chain Reaction Assays for Detection and Quantification of Enterotoxigenic Escherichia coli (ETEC) Heat Labile and Heat Stable Toxin Genes in Travelers' Diarrhea Samples

“…30,31 In the case of a diarrheal sample, however, a low ETEC toxin gene titer may indicate that ETEC is not necessarily the cause of disease. Subjects who remain asymptomatic upon rechallenge with 31 and ETEC has been isolated from asymptomatic subjects 32 and was detected at low titer in one of our control healthy traveler samples (Tables 3 and 4). Twenty of the clinical samples we tested had 10 5 ETEC cells per stool sample (Table 4) suggesting that, although ETEC is present, it may not be the source of the diarrhea given the estimated quantities of toxin genes.…”

Characterization of Mucosal Immune Responses to Enterotoxigenic Escherichia coli Vaccine Antigens in a Human Challenge Model: Response Profiles after Primary Infection and Homologous Rechallenge with Strain H10407

“…The protocol was conducted under BB-IND 12,243 at the Center for Immunization Research (CIR), Johns Hopkins Bloomberg School of Public Health. Approval to conduct the study was provided by the Western Institutional Review Board (Olympia, WA) for the Johns Hopkins Bloomberg School of Public Health, the Institutional Biosafety Committee of the Johns Hopkins Institutions, and PATH (19).…”

“…Pre-and postchallenge venous blood samples were collected the same days as the ALS samples and processed for serum as described previously (19). A serum response was defined as a Ն2.5-fold increase over the baseline.…”

“…The investigations outlined in this report attempted to take advantage of ongoing ETEC model refinement work (19) at the Johns Hopkins School of Public Health (JHSPH) to gain a better insight into the nature, kinetics, and magnitude of mucosal immune responses to ETEC lipopolysaccharide (LPS), heat-labile toxin B subunit (LTB), and CFA/I antigens in naive and immune subjects. This information will be of value to future ETEC vaccine development efforts since it will provide an immunological benchmark to help assess new candidate ETEC vaccines moving into early clinical development.…”

A systematic review of experimental infections with enterotoxigenic Escherichia coli (ETEC)

“…In addition to the significant diarrheal output, H10407 is associated with more severe concurrent signs and symptoms with fever and vomiting reported in a relatively high proportion of subjects compared to volunteers challenged with other ETEC strains. Efforts are ongoing to evaluate lower inoculum doses of H10407 [44]. These studies may identify lower inoculum doses that retain a high diarrhea attack rate yet result in a lower frequency of high volume output and less severe concurrent symptoms.…”