First-of-its-kind vaccine protects children from deadly E. coli infections

First-of-its-kind vaccine protects children from deadly intestinal infections

By Sahas Mehra edited by Tanya Lewis

Infections from enterotoxigenic Escherichia coli (ETEC) bacteria are the most common cause of travelers’ diarrhea, and they commonly cause childhood diarrhea in low-income regions. In children below the age of five, whose immune systems are still developing, the infections can lead to malnourishment; they cause up to 42,000 deaths annually. Soon there may be a vaccine to protect against these infections.

In the Lancet Infectious Diseases last month, scientists shared the results of the first study to evaluate the safety and efficacy of an ETEC-controlling vaccine in a large pediatric population in Gambia. The vaccine—called ETVAX—is among several in development to reduce ETEC infections in both adults and children. ETVAX provided immunity against the pathogens and did not have any adverse side effects.

ETEC bacteria have “adhesin” proteins that enable them to attach themselves to the intestinal mucosa. The bacteria then release toxins, which lead to watery diarrhea and abdominal cramping. In low-income countries, a lack of access to sanitation and clean drinking water increases the risk of E. coli infections, resulting in more childhood fatalities and higher health care costs.

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An approved oral cholera vaccine called Dukoral provides partial protection against some forms of ETEC diarrhea, but “at present, there is no approved E. coli vaccine available for protection against any type of E. coli infections in humans,” says immunologist Ann-Mari Svennerholm of the University of Gothenburg in Sweden, who co-authored the study. She notes that ETVAX is the first to show significant protection against E. coli infections in people.

Oral cholera vaccines have “only a few different types of bacteria” to build protection against, Svennerholm says. ETEC bacteria, by contrast, have 26 distinct adhesin proteins and two kinds of toxins. For ETVAX, her research team created a formula that used the four most common adhesin proteins, which are found on 80 percent of all enterotoxigenic E. coli. They combined the proteins with an inert part of a toxin and a component that stimulates intestinal immune responses. ETVAX was created by Scandinavian Biopharma. Some of the study authors hold commercial rights to the vaccine and might receive a small royalty if it eventually becomes a commercial product.

Previous studies found that ETVAX was safe and effective in smaller pediatric populations in Bangladesh and Zambia. [TL1] For the recent trial, 4,936 children in Gambia between the ages of six and 18 months received three doses of either the oral vaccine or a placebo, with follow-ups taking place over two years. The researchers randomly assigned children to get either the vaccine or the placebo, and the investigators didn’t know who received which one.

ETVAX increased antibodies against multiple ETEC adhesin proteins, especially after the third dose. It reduced moderate-to-severe ETEC diarrhea episodes by a modest 26 percent compared with the placebo group when ETEC cases with co-infections from common gut pathogens such as Shigella, Cryptosporidium, rotavirus or a type of norovirus were excluded.

When the researchers included these co-infections, ETVAX reduced moderate-to-severe diarrhea from ETEC in all children by 48 percent and in infants younger than nine months by 68 percent. This highlights the importance of immunizing young infants who have not acquired natural immunity to intestinal pathogens. Further, co-author Thomas Wierzba, a professor of infectious diseases at Wake Forest School of Medicine, explains that ETVAX reduced moderate-to-severe diarrhea from viruses, bacteria or other parasites by 21 percent. This suggests the vaccine provides partial protection against multiple gut pathogens.

Epidemiologist David Sack of the John Hopkins Bloomberg School of Public Health, who was not involved in the paper, believes it is a “high-quality study” because it used different outcomes to evaluate the vaccine. He notes that the mechanisms behind the cross protection against other pathogens requires further investigation, however. Amira Roess, a professor of global health and epidemiology at George Mason University’s College of Public Health, says the research supports future clinical trials, but further work is needed to better characterize the causes of diarrheal diseases in participants.

ETVAX will soon be evaluated in a European Medicines Agency–approved phase 3 trial, which will enroll 5,800 infants between the ages of six and nine months from low- and middle-income countries.

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