Progress and hurdles in the development of vaccines against enterotoxigenic Escherichia coli in humans

Abstract

Diarrhea is the second leading cause of death in children younger than 5 years. Enterotoxigenic Escherichia coli (ETEC) strains are the most common bacterial cause of diarrhea in young children living in endemic countries and children and adults traveling to these areas. Pathogenesis of ETEC diarrhea has been well studied, and the key virulence factors are bacterial colonization factor antigens and enterotoxins produced by ETEC strains. Colonization factor antigens mediate bacteria attachment to host small intestinal epithelial cells and subsequent colonization, whereas enterotoxins including heat-labile and heat-stable toxins disrupt fluid homeostasis in host epithelial cells, which leads to fluid and electrolyte hypersecretion and diarrhea. Vaccines stimulating host anti-adhesin immunity to block ETEC attachment and colonization and also antitoxin immunity to neutralize enterotoxicity are considered optimal for prevention of ETEC diarrhea. Vaccines under development have been designed to stimulate local intestinal immunity and are either oral vaccines or transcutaneous vaccines. A cholera vaccine (Dukoral®) does stimulate anti-heat-labile toxin immunity and is licensed for short-term protection of ETEC diarrhea in travelers in some countries. Newer experimental ETEC vaccine candidates are being developed with hope to provide long-lasting and more broad-based protection against ETEC. Some have shown promising results in safety and immunogenicity studies and are approaching field trials for efficacy. A key problem is the development of a vaccine that is both practical and inexpensive so that it can be affordable for use in poor countries where it is needed.

Keywords::

• diarrhea
• enterotoxigenic Escherichia coli
• ETEC
• subunit vaccine
• whole-cell vaccine

Acknowledgements

The authors wish to thank AL Bourgeois from PATH for providing updated enterotoxigenic Escherichia coli literatures including the PATH and BIO Ventures for Global Health article: ‘A Case for Investment in Enterotoxigenic E. coli Vaccines’ (March 2011).

Financial & competing interests disclosure

The authors have been involved in human volunteer trials of the killed and live-attenuated whole-cell enterotoxigenic Escherichia coli vaccine candidates, the development of antitoxin vaccine candidates using heat-labile and heat-stable toxin fusions, and development and application of the removable intestinal tie adult rabbit diarrhea (RITARD), pig animal challenge models and human challenge models as well. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.