The first-of-its-kind vaccine protects children against deadly E. coli infections

The first vaccine of its kind protects children against deadly intestinal infections

By Sahas Mehra edited by Tanya Lewis

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

IN Lancet Infectious Diseases last month, researchers shared the results of the first study to evaluate the safety and efficacy of an ETEC-controlling vaccine in a large pediatric population in The 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 had no adverse side effects.

ETEC bacteria have “adhesin” proteins that enable them to stick to the intestinal lining. The bacteria then release toxins, which lead to watery diarrhea and stomach cramps. In low-income countries, lack of access to sanitary facilities and clean drinking water increases the risk of E.coli infections, resulting in more childhood fatalities and higher healthcare costs.

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An approved oral cholera vaccine called Dukoral provides partial protection against some forms of ETEC diarrhea, but “currently there is no approved E.coli vaccine available to protect against all types E.coli infections in humans, says immunologist Ann-Mari Svennerholm at Gothenburg University in Sweden, who was a co-author of the study. She notes that ETVAX is the first to show significant protection against E.coli infections in humans.

Oral cholera vaccines have “only a few different types of bacteria” to build protection against, says Svennerholm. ETEC bacteria, on the other hand, have 26 different adhesin proteins and two types 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 enterotoxigens E.coli. They combined the proteins with an inert part of a toxin and a component that stimulates the gut’s immune response. ETVAX was made by Scandinavian Biopharma. Some of the study authors have commercial rights to the vaccine and may receive a small royalty if it eventually becomes a commercial product.

Previous studies found ETVAX to be safe and effective in smaller pediatric populations in Bangladesh and Zambia. (TL1) For the recent study, 4,936 children in The Gambia between six and 18 months received three doses of either oral vaccine or placebo, with follow-up over two years. The researchers randomly assigned children to receive either the vaccine or a placebo, and the investigators did not know who received which.

ETVAX increased antibodies to several ETEC adhesin proteins, particularly after the third dose. It reduced moderate to severe ETEC diarrhea episodes by a modest 26 percent compared to the placebo group when ETEC cases with co-infections from common enteric 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 enteric pathogens. Furthermore, co-author Thomas Wierzba, 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 that the vaccine provides partial protection against several enteric 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 require further investigation. Amira Roess, 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 illness in the participants.

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

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