ETECvac: Development of a human challenge model to test enterotoxigenic E. coli vaccines candidates based on the heat-stable toxin

Diarrhea causes ill health and malnutrition and is the second most common cause of death among children. One of the most important causes of diarrhea in children under age five in developing countries is enterotoxigenic E. coli (ETEC) secreting the heat-stable toxin ST. Currently available prototype ETEC vaccines target colonization factors and the heat-labile toxin, but not ST. These have so far failed to confer adequate protection. Development of an ST-based ETEC vaccine would be very beneficial because it targets the ETEC types responsible for diarrheal disease in low-income settings.

The overall ETECvac project is based on a unique and comprehensive ST mutational library, established at the University of Bergen (UiB) and NORCE (external link), which allowed an unprecedented and detailed study of the toxin's properties. The main aims of the ETECvac project were to design safe and protective ST vaccine candidates and to establish the first human challenge model for estimating the protective efficacy of an ST vaccine.

The research was conducted at the UiB, NORCE and Haukeland University Hospital (HUH). The human challenge model work was done in collaboration between HUH and UiB (Department of Clinical Science and Department of Global Public Health and Primary Care). We sought to establish a human challenge model which could enable rapid evaluation of ST based vaccine candidate we were developing. Two different ETEC strains were tested at oral ingestion doses from 10^6 to 10^10 CFU resuspended in bicarbonate solution. Both strains were producers of ST as the only toxin. We enrolled a total of 30 human volunteers. 

The project resulted in a ST based vaccine candidate ready for further development by pharmaceutical industry. A challenge model based on one of the ETEC strains, TW10722, was found to fulfill the criterium of producing diarrhea in 70% of the volunteers. Saliva, serum, intestinal lavage and immune cells collected during the human experimental infections have been used in downstream studies of microbiological and immunological features of human ETEC infection.