Enterotoxigenic Escherichia coli (ETEC) vaccines: Priority activities to enable product development, licensure, and global access

Abstract

Diarrhoeal disease attributable to enterotoxigenic Escherichia coli (ETEC) causes substantial morbidity and mortality predominantly in paediatric populations in low- and middle-income countries. In addition to acute illness, there is an increasing appreciation of the long-term consequences of enteric infections, including ETEC, on childhood growth and development. Provision of potable water and sanitation and appropriate clinical care for acute illness are critical to reduce the ETEC burden. However, these interventions are not always practical and may not achieve equitable and sustainable coverage. Vaccination may be the most cost-effective and equitable means of primary prevention; however, additional data are needed to accelerate the investment and guide the decision-making process for ETEC vaccines. First, to understand and quantify the ETEC disease burden, additional data are needed on the association between ETEC infection and physical and cognitive stunting as well as delayed educational attainment. Furthermore, the role of inappropriate or inadequate antibiotic treatment of ETEC-attributable diarrhoea may contribute to the development of antimicrobial resistance (AMR) and needs further elucidation. An ETEC vaccine that mitigates acute diarrhoeal illness and minimizes the longer-term disease manifestations could have significant public health impact and be a cost-effective countermeasure. Herein we review the ETEC vaccine pipeline, led by candidates compatible with the general parameters of the Preferred Product Characteristics (PPC) recently developed by the World Health Organization. Additionally, we have developed an ETEC Vaccine Development Strategy to provide a framework to underpin priority activities for researchers, funders and vaccine manufacturers, with the goal of addressing globally unmet data needs in the areas of research, product development, and policy, as well as commercialization and delivery. The strategy also aims to guide prioritization and co-ordination of the priority activities needed to minimize the timeline to licensure and use of ETEC vaccines, especially in in low- and middle-income countries, where they are most urgently needed.

Keywords: Childhood growth and development; Diarrhoeal diseases; Disease burden; Enterotoxigenic Escherichia coli (ETEC); Vaccine research.

Fig. 1

Association between enteric pathogens detected by quantitative PCR in monthly non-diarrheal stool samples and stool myeloperoxidase in the multisite MAL-ED birth cohort study. Estimates are per tenfold increase in pathogen quantity from a single linear mixed-effects model including the quantity of each pathogen, sex, and age as fixed effects and site and subject as random effects. A total of 18,365 monthly non-diarrheal stools from 1715 children followed until 2 years of age were included, all of which had valid qPCR results for all included pathogens and were tested for myeloperoxidase (MPO; measured in nanograms per milliliter), a marker of neutrophil activity in the intestinal mucosa (Alpco). (Unpublished data provided courtesy of James Platts-Mills, University of Virginia).