Experimental Infection of Human Volunteers with the Heat-Stable Enterotoxin-Producing Enterotoxigenic Escherichia coli Strain TW11681.

Sunniva Todnem Sakkestad,Hans Steinsland,Astrid Rykkje Heien,Hanne Søyland,Halvor Sommerfelt,Kurt Hanevik,Marit Gjerde Tellevik,Elisabeth Kleppa,Steinar Skrede,Marianne Sævik,Eileen M Barry,Kristine Lillebø

doi:10.3390/pathogens8020084

Abstract

Infection with enterotoxigenic Escherichia coli (ETEC) producing the heat-stable enterotoxin (ST) is one of the most important causes of childhood diarrhoea in low- and middle-income countries. Here, we undertook a controlled human infection model (CHIM) study to investigate whether ST-producing ETEC strain TW11681 would be suitable for testing the protective efficacy of new ST-based vaccine candidates in vaccine challenge models. In groups of three, nine volunteers ingested 1 × 106, 1 × 107, or 1 × 108 colony-forming units (CFU) of TW11681. Flow cytometry-based assays were used to measure CD4+ T cell responses and antibody levels targeting virulence factors expressed by the strain. We found that infection with TW11681 elicited few and mild symptoms, including mild diarrhoea in two volunteers, both of whom ingested 1 × 106 CFU. Averaged across all volunteers, the CD4+ T cell responses specific for E. coli YghJ mucinase peaked 10 days after infection (3.2-fold (p = 0.016)), while the CD4+ T cell responses specific for Colonization Factor Antigen I (CFA/I) major fimbrial subunit (CfaB) peaked after 28 days (3.6-fold (p = 0.063)). The serum CfaB-specific anti-IgA and anti-IgG/IgM levels were significantly increased and peaked 3 months after infection. Both remained elevated for the duration of the 12-month follow-up. The corresponding anti-YghJ serological response was strongest after 10 days, although a significant increase was seen only for IgA levels (3.2-fold (p = 0.008)). In conclusion, due to its low diarrhoea attack risk, TW11681 is probably not suitable for testing the efficacy of new vaccines in human challenge studies at doses 1 × 106 to 1 × 108. However, the strain may still be useful in CHIMs for studying ETEC host-pathogen interactions.

Highlights

Infection with enterotoxigenic Escherichia coli (ETEC) is a major cause of diarrhoeal disease in lowand middle-income countries (LMICs) [1]
ETEC was detected in the stools for 5–8 days (3 days for volunteer EV14) after they ingested the dose, suggesting all volunteers were successfully colonized by the challenge strain
In this study we evaluated whether the stable toxin (ST)-only ETEC strain TW11681 could be suitable for use in a vaccine challenge model

Summary

Introduction

Infection with enterotoxigenic Escherichia coli (ETEC) is a major cause of diarrhoeal disease in lowand middle-income countries (LMICs) [1]. E. coli that produce one or both of the two protein enterotoxins called heat-stable toxin (ST), which is small and non-immunogenic, and heat-labile toxin (LT), which is large and immunogenic. Infections with ST-producing ETEC strains (with or without LT) are among the most important bacterial causes of moderate-to-severe diarrhoea in children under 5 years of age in LMICs. ST-ETEC is associated with an increased risk of death [2]. Developing an effective ST-based vaccine, represents a promising strategy to confer broad protection against ETEC-induced diarrhoea. Two variants of ST exist, called porcine ST (STp) and human ST (STh). STh-producing ETEC are more pathogenic for young children in LMICs than STp-producing ETEC [3,4]

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Discussion

Conclusion