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Fast-Acting Vaccine and Probiotic Combat Cholera in Animals

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The new treatments tested in animals appear to keep cholera bacteria from taking root in the intestines. | Sanofi Pasteur

Scientists testing a new fast-acting vaccine and a probiotic treatment have found that both interventions reduce the severity of cholera infections in rabbits and mice, according to a pair of new studies published in the June 13 issue of Science Translational Medicine.

Although still in the early stages, the results may pave the way for clinical trials in humans, and could give health authorities new tools and strategies for curbing the spread and severity of cholera, a disease that results in an estimated 2.9 million cases and 95,000 deaths each year around the world, according to the CDC website.

Cholera, caused by the Vibrio cholerae bacterium, is an infectious illness that causes severe diarrhea and vomiting. It spreads through food and water contaminated by feces from an infected individual. The disease is easily treatable with rehydration therapies and has been largely eliminated in the developed world. However, cholera still runs rampant in areas of the developing world that lack adequate sanitation and access to safe water.

Regions that have undergone natural disasters or political instability are particularly vulnerable to cholera epidemics due to the resulting breakdown of healthcare systems. The ongoing outbreak in Yemen — the largest cholera epidemic in history — has sickened more than 1,100,000 people, according to a WHO bulletin. The origins of the epidemic can be traced back to the damage inflicted by the Yemeni civil war, which has shattered the country's health infrastructure.

A Faster-Acting Vaccine

Health authorities have successfully developed oral vaccines for cholera as a preemptive measure in at-risk populations, according to Matthew Waldor, a professor of medicine at Brigham and Women's Hospital in Boston, Massachusetts and co-author of the first study. These vaccines are safe for use and are 50% to 80% effective in adults for three to five years, he said.

However, current oral vaccines are much less effective in children, who represent half of all cholera fatalities, he said. Additionally, they can take over a week to induce immunity, limiting their effectiveness during cholera epidemics that often explode within several days.

"We were motivated by the need for a modern cholera vaccine that is effective across all age groups and deployable as a single, easily-administered dose," Waldor said. "Our work also indicated that the ideal cholera vaccine is one that acts rapidly, protecting within hours of administration rather than days."

With the goal of developing a faster-acting vaccine, Waldor and colleagues engineered a weakened strain of cholera called HaitiV — based on the strain responsible for the Haitian outbreak that arose after the country's 2010 earthquake — and used it as the basis for a live oral vaccine. To make HaitiV safe for use, they removed several genes that are responsible for the bacteria's production of dangerous toxins.

The model developed by Waldor's team showed that during a simulated cholera outbreak in a population of 100,000 people, a vaccine that acts in one day could prevent thousands of additional cases when compared to a traditional vaccine that acts over ten days.

The researchers then administered the vaccine to a group of infant rabbits. One day later, they exposed both the vaccinated rabbits and a separate control group of animals to lethal doses of cholera bacteria.

The unvaccinated rabbits developed severe diarrhea and succumbed to infection in less than a day, Waldor said. However, most of the vaccinated rabbits had no diarrhea, and those that did developed symptoms slower compared to untreated animals.

The speed with which the vaccine granted protection suggests it works separately from the adaptive immune response, the portion of the immune system that is targeted by most vaccines and develops over days or weeks. The authors aren't sure how the vaccine confers immunity, but they think that it could work through a different route than adaptive immunity, such as preventing the pathogen from accessing intestinal sites.

The team also designed a modeling experiment to see how a similar vaccine would influence the outcome of a cholera epidemic in humans. The model showed that during a simulated cholera outbreak in a population of 100,000 people, a vaccine that acts in one day could prevent thousands of additional cases when compared to a traditional vaccine that acts over ten days.

Waldor said the research team plans to administer HaitiV to human volunteers to ensure it is safe and can elicit a protective immune response. From there, they will design a trial that includes vaccination of volunteers followed by exposure to cholera bacteria, he said.

Harnessing the Microbiome to Fight Cholera

In another study, a separate research group explored the possibility of harnessing friendly gut bacteria to make it harder for the cholera bacterium to establish itself in the intestines.

Their goal was to develop a treatment for cholera that could both prevent infections and serve as a diagnostic tool for disease surveillance, according to Andres Cubillos-Ruiz, a postdoctoral associate at MIT and co-author of the study.

Cubillos-Ruiz and colleagues zeroed in on a probiotic bacterial species named Lactococcus lactis, which is commonly found in fermented milk products. The bacteria caught their attention because it produces lactic acid, a compound that inhibits the growth of cholera.

Administering L. lactis to an individual at risk of cholera infection, they suggested, could increase levels of lactic acid in the gastrointestinal tract, making the digestive environment more hostile to cholera growth and reproduction.

"When fully optimized for human use, these probiotics can be distributed as part of humanitarian aid efforts in natural disaster-stricken or war-torn areas to prevent and monitor potential cholera outbreaks."

Andres Cubillos-Ruiz

"Our proposed probiotic intervention is meant to act one step ahead [of cholera] by protecting against colonization of the pathogen," Cubillos-Ruiz said.

The authors found that orally administrating L. lactis to infant mice infected with cholera reduced the amount of cholera bacteria in the intestines and increased the animals' chance of survival to 85%, compared to 46% in control mice.

Seeking to build on their success, they also engineered a strain of L. lactis that produces an enzyme upon sensing the presence of cholera bacteria nearby. This enzyme showed up in stool samples of infected mice and changed colors after being exposed to a compound called nitrocefin, serving as a visual marker that cholera bacteria were present in the digestive system.

The research group believes this diagnostic could serve as a warning tool and a potential method to improve disease surveillance in at-risk populations. For example, an infected individual with a positive stool sample could quickly seek medical attention before symptoms appear, Cubillos-Ruiz said.

Detecting these developing cases could also alert public health authorities to a potential outbreak in the making. Officials could respond by isolating the patient in a timely manner and rooting out any potential contamination of communal water sources, he said.

The scientists ultimately envision that probiotic-based treatments could grant health agencies and humanitarian organizations a new angle of attack against cholera epidemics unfolding in vulnerable regions.

"When fully optimized for human use, these probiotics can be distributed as part of humanitarian aid efforts in natural disaster-stricken or war-torn areas to prevent and monitor potential cholera outbreaks," Cubillos-Ruiz said.

Author

Joseph Cariz