Vaccines for preventing enterotoxigenic Escherichia coli (ETEC) diarrhoea

Abstract

Background

Infection with enterotoxigenic Escherichia coli (ETEC) bacteria is a common cause of diarrhoea in adults and children in developing countries and is a major cause of 'travellers' diarrhoea' in people visiting or returning from endemic regions. A killed whole cell vaccine (Dukoral®), primarily designed and licensed to prevent cholera, has been recommended by some groups to prevent travellers' diarrhoea in people visiting endemic regions. This vaccine contains a recombinant B subunit of the cholera toxin that is antigenically similar to the heat labile toxin of ETEC. This review aims to evaluate the clinical efficacy of this vaccine and other vaccines designed specifically to protect people against diarrhoea caused by ETEC infection.

Objectives

To evaluate the efficacy, safety, and immunogenicity of vaccines for preventing ETEC diarrhoea.

Search methods

We searched the Cochrane Infectious Disease Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, LILACS, and http://clinicaltrials.gov up to December 2012.

Selection criteria

Randomized controlled trials (RCTs) and quasi‐RCTs comparing use of vaccines to prevent ETEC with use of no intervention, a control vaccine (either an inert vaccine or a vaccine normally given to prevent an unrelated infection), an alternative ETEC vaccine, or a different dose or schedule of the same ETEC vaccine in healthy adults and children living in endemic regions, intending to travel to endemic regions, or volunteering to receive an artificial challenge of ETEC bacteria.

Data collection and analysis

Two authors independently assessed each trial for eligibility and risk of bias. Two independent reviewers extracted data from the included studies and analyzed the data using Review Manager (RevMan) software. We reported outcomes as risk ratios (RR) with 95% confidence intervals (CI). We assessed the quality of the evidence using the GRADE approach.

Main results

Twenty‐four RCTs, including 53,247 participants, met the inclusion criteria. Four studies assessed the protective efficacy of oral cholera vaccines when used to prevent diarrhoea due to ETEC and seven studies assessed the protective efficacy of ETEC‐specific vaccines. Of these 11 studies, seven studies presented efficacy data from field trials and four studies presented efficacy data from artificial challenge studies. An additional 13 trials contributed safety and immunological data only.

Cholera vaccines

The currently available, oral cholera killed whole cell vaccine (Dukoral®) was evaluated for protection of people against 'travellers' diarrhoea' in a single RCT in people arriving in Mexico from the USA. We did not identify any statistically significant effects on ETEC diarrhoea or all‐cause diarrhoea (one trial, 502 participants, low quality evidence).

Two earlier trials, one undertaken in an endemic population in Bangladesh and one undertaken in people travelling from Finland to Morocco, evaluated a precursor of this vaccine containing purified cholera toxin B subunit rather than the recombinant subunit in Dukoral®. Short term protective efficacy against ETEC diarrhoea was demonstrated, lasting for around three months (RR 0.43, 95% CI 0.26 to 0.71; two trials, 50,227 participants). This vaccine is no longer available.

ETEC vaccines

An ETEC‐specific, killed whole cell vaccine, which also contains the recombinant cholera toxin B‐subunit, was evaluated in people travelling from the USA to Mexico or Guatemala, and from Austria to Latin America, Africa, or Asia. We did not identify any statistically significant differences in ETEC‐specific diarrhoea or all‐cause diarrhoea (two trials, 799 participants), and the vaccine was associated with increased vomiting (RR 2.0, 95% CI 1.16 to 3.45; nine trials, 1528 participants). The other ETEC‐specific vaccines in development have not yet demonstrated clinically important benefits.

Authors' conclusions

There is currently insufficient evidence from RCTs to support the use of the oral cholera vaccine Dukoral® for protecting travellers against ETEC diarrhoea. Further research is needed to develop safe and effective vaccines to provide both short and long‐term protection against ETEC diarrhoea.

Vaccines for preventing diarrhoea caused by enterotoxigenic Escherichia coli bacteria

Enterotoxigenic E. coli (ETEC) is a type of bacteria that can infect both children and adults, causing diarrhoea. In particular, it affects people in developing countries. However, it is also a major cause of 'travellers' diarrhoea' in people visiting or returning from regions where this infection is common. It is transmitted from person to person by eating or drinking unclean food or water. Typically it causes watery diarrhoea, with abdominal pains and vomiting, that can last for several days. Vaccines are being considered as a way to prevent diarrhoea caused by ETEC bacteria. ETEC bacteria share some similarities with the bacteria that cause cholera. In this review, we examined the effectiveness of either vaccines designed to prevent cholera or vaccines designed specifically to prevent ETEC infection for preventing ETEC diarrhoea. We compared these vaccines against the use of a control vaccine (either an inert vaccine or a vaccine normally given to prevent an unrelated infection), no intervention, an alternative ETEC vaccine, or a different dose or schedule of the same ETEC vaccine.

We examined the research published up to 07 December 2012. We included 24 randomized controlled trials and 53,247 participants in this review. Four studies assessed the use of oral cholera vaccines to prevent diarrhoea caused by ETEC and eight trials assessed the use of ETEC‐specific vaccines to prevent diarrhoea. Seven studies presented data from field trials and four studies presented data from studies where people were artificially infected with ETEC bacteria. Also, 13 trials gave safety and immunological data only.

There is currently insufficient evidence to support the use of the oral cholera vaccine Dukoral® to protect travellers against ETEC diarrhoea. Based on a single trial in people travelling from the USA to Mexico, the oral cholera vaccine Dukoral® may have little or no effect in preventing ETEC diarrhoea (one trial, 502 participants, low quality evidence). Two earlier trials, one undertaken in an endemic population in Bangladesh and one undertaken in people travelling from Finland to Morocco, evaluated a precursor of the oral cholera vaccine Dukoral®. Short term protection against ETEC diarrhoea was demonstrated, lasting for around three months (RR 0.43, 95% CI 0.26 to 0.71; two trials, 50,227 participants). However, this vaccine is no longer available.

An ETEC‐specific, killed whole cell vaccine, which also contains the recombinant cholera toxin B‐subunit, was evaluated in people travelling from the USA to Mexico or Guatemala, and from Austria to Latin America, Africa, or Asia. There were no statistically significant differences in ETEC‐specific diarrhoea or all‐cause diarrhoea (two trials, 799 participants) found and the vaccine was associated with increased vomiting (RR 2.0, 95% CI 1.16 to 3.45; nine trials, 1528 participants). The other ETEC‐specific vaccines in development have not yet demonstrated clinically important benefits. Further research is needed to develop safe and effective vaccines to provide both short and long‐term protection against ETEC diarrhoea.