Implications of enterotoxigenic Escherichia coli genomics for vaccine development

Abstract

Enterotoxigenic Escherichia coli (ETEC) is a major cause of morbidity and mortality caused by diarrhea in children less than 5 years of age in low- and middle-income countries. Despite a wealth of research elucidating the mechanisms of disease, the immunological responses and vaccine development, ETEC is still relatively uncharacterized when it comes to regulation of virulence and detailed immune mechanisms. The recent emergence of next-generation sequencing now offers the possibility to screen genomes of ETEC strains isolated globally to identify novel vaccine targets in addition to those already established. In this review, we discuss how recent findings on ETEC genomics using novel sequencing techniques will aid in finding novel protective antigens that can be used in vaccine approaches.

Keywords:

• colonization factor
• enterotoxigenic Escherichia coli
• ETEC
• ETEC vaccine
• genomics
• next-generation sequencing
• oral vaccine

Acknowledgements

The authors thank Professors G Dougan, N Thomson and T Connor at the Wellcome Trust Sanger Institute UK for financial and technical support of genome sequencing data presented. The authors also would like to thank former and present colleagues at University of Gothenburg who have contributed to sequencing data.

Financial & competing interests disclosure

This work was funded by the Swedish foundation for Strategic Research, the Swedish Research Council and the PATH EVI program. A-M Svennerholm is a shareholder in Gotovax AB that may receive a small royalty on the sales of ETEC vaccine if it becomes a commercial product. A-M Svennerholm also has a patent in the area. 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.

Key issues

• Enterotoxigenic Escherichia coli (ETEC) remains to be a major cause of infantile diarrhea in the developing world and causes disease by secretion of either one or both of the enterotoxins stable toxin and labile toxin as well as by adhesion to the epithelium by a variety of colonization factors (CFs).

• Shifts in toxin–CF profiles may occur but several of the predominant toxin–CF combinations seem to be stable and of clonal origin and are reproducibly isolated in Africa, Asia and the Americas over time.

• The most promising vaccine candidates are still vaccines expressing or containing labile toxin antigen and CFs.

• The recent advance in whole genome sequencing of ETEC offers the possibility to search genomes for novel prevalent vaccine candidate antigens.

• Conserved surface-exposed antigens specific for ETEC or for ‘all’ pathogenic E. coli should be identified and might be included in future E. coli candidate vaccines.

• Identification of conserved pangenome E coli putative vaccine antigens must be thoroughly compared with commensal E. coli of all phylogroups.

• A search for novel colonization factors in genomes that lack described CFs is in progress since ETEC CFs would fulfill requirements for an ETEC vaccine with a broad coverage.

• Current vaccines may be improved by additional ETEC-specific conserved antigens identified by reverse vaccinology approaches.

• Potential novel antigens to be included in future vaccines should be pathogen specific, surface exposed and immunogenic.