Live attenuated enterotoxigenic Escherichia coli (ETEC) vaccine with dmLT adjuvant protects human volunteers against virulent experimental ETEC challenge.

BACKGROUND: There is no licensed vaccine against enterotoxigenic Escherichia coli (ETEC), a major cause of diarrhea-associated morbidity and mortality among infants and children in low-income countries and travelers. The results of this vaccination/challenge study demonstrate strong protection by an attenuated ETEC vaccine candidate, ACE527, when co-administered with a mucosal adjuvant, the double-mutant heat-labile toxin (dmLT) of ETEC. METHODS: Sixty healthy adults participated in a randomized, placebo-controlled, double-blind study with three doses of lyophilized ACE527 (∼3 × 109 of each strain per dose) administered orally with or without dmLT adjuvant (25 µg/dose). Six months later, 36 of these volunteers and a control group of 21 unvaccinated volunteers were challenged with virulent ETEC strain H10407. The primary outcome was severe diarrhea, defined as passing >800 g of unformed stools during the inpatient period following challenge. FINDINGS: The vaccine was well tolerated and induced robust immune responses to key antigens. The protective efficacy (PE) against the primary outcome of severe diarrhea was 65.9% (95% confidence interval [CI] 5.4-87.7, p = 0.003). Among subjects receiving the adjuvanted vaccine, the attack rate of severe diarrhea was 23.1, while in unimmunized controls it was 67.7%. The PE against diarrhea of any severity was 58.5% (95% CI 3.8- 82.1, p = 0.016). There was a strong inverse correlation between shedding of the vaccine strain after either of the first two doses and absence of severe diarrhea upon challenge (RR = 0.29, 95% CI 0.08-1.05, p = 0.041). Challenge strain shedding was 10-fold lower in those receiving the adjuvant than in those receiving vaccine alone. The unadjuvanted vaccine was not protective (PE = 23.1%). INTERPRETATION: The results of this study support further development of ACE527 + dmLT as a vaccine for children in endemic countries and travelers. This is the first clinical demonstration that dmLT can contribute significantly to vaccine efficacy and may warrant testing with other oral vaccines. (ClinicalTrials.gov registration: NCT01739231).

Current perceptions of travelers' diarrhea treatments and vaccines: results from a postal questionnaire survey and physician interviews.

BACKGROUND: Travelers' diarrhea (TD) occurs at high frequency in individuals from industrialized countries visiting destinations in nonindustrialized countries and may result in chronic complications such as Guillain-Barré syndrome. METHODS: We distributed a questionnaire requesting information on physicians' perceptions of currently available TD products, hypothesized TD vaccines, and aspects of travelers' behavior. Some physicians also were interviewed by telephone. RESULTS: We obtained completed questionnaires from named individuals at 68 UK/US clinics. These individuals reported seeing a total of approximately 76,500 travelers per year, and estimated that 61% (UK) and 77% (US) of travelers present 2 weeks or more predeparture. More US (92%) than UK (43%) travelers are advised to purchase TD products. In both countries, 85% of travelers would be prescribed an ideal TD vaccine, but only approximately 47% (UK) and approximately 65% (US) would purchase this vaccine. About 80% of physicians would recommend an hypothesized 100% effective Campylobacter vaccine for travelers visiting regions where 30% of TD cases are caused by Campylobacter. CONCLUSIONS: Physicians support the concept of TD vaccines, including campylobacteriosis vaccines. An ideal TD vaccine might be purchased by up to 16% (UK) and 28% (US) of relevant travelers. A 100% effective Campylobacter vaccine might be purchased by over 2 million UK/US travelers per year.