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June 14, 2018

Probiotic, Live Vaccine Both Curb Cholera

Some species of Vibrio bacteria (blue) can cause cholera in humans. A version of Vibrio cholerae designed to be harmless may one day protect people against the dangerous form of the bacteria. [Tina Carvalho/University of Hawaii at Manoa/CC BY 2.0]

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    Cell dish experiments showed that L. lactis had an antibacterial effect when grown on a layer of cholera bacteria. A strain of L. lactis deficient in lactic acid production (L. lactis ?ldh) did not show the same effect. [N. Mao et al., Science Translational Medicine (2018)]

    New probiotic and vaccine-based interventions have been shown to suppress cholera in animal models, indicated two research articles, both of which appeared June 13 in the journal Science Translational Medicine. The probiotic intervention, developed by a team of scientists based at MIT, consists of a mix of natural and engineered Lactococcus bacteria. The vaccine-based intervention, developed by a team of scientists based at Brigham and Women’s Hospital (BMH) and the Howard Hughes Medical Institute (HHMI), is a genetically “defanged” version of HaitiWT, a particularly virulent strain of Vibrio cholerae.

    The MIT team's new probiotic mix could be consumed regularly as a preventative measure in regions where cholera is common, or used to treat people soon after infection occurs, said James Collins, Ph.D., a professor of biomedical engineering and the senior author of one of the new STM articles. In this article, “Probiotic Strains Detect and Suppress Cholera in Mice,” Collins and colleagues describe their probiotic-based strategy to promote colonization resistance and point-of-need diagnosis of cholera.

    "Our goal was to use synthetic biology to develop an inexpensive means to detect and diagnose as well as suppress or treat cholera infections," said Dr. Collins. "If one could inexpensively and quickly track the disease and treat it with natural or engineered probiotics, it could be a game-changer in many parts of the world."

    “Oral administration of Lactococcus lactis, a common dietary fermentative bacterium, reduced intestinal V. cholerae burden and improved survival in infected infant mice through the production of lactic acid,” the article detailed. “Furthermore, we engineered an L. lactis strain that specifically detects quorum-sensing signals of V. cholerae in the gut and triggers expression of an enzymatic reporter that is readily detected in fecal samples.”

    The BMH/HHMI team’s vaccine essentially uses a toothless V. cholerae as a protective shield. The vaccine consists of harmless, lab-designed bacteria don't cause cholera. Instead, they seem to function somewhat like a probiotic, preventing the dangerous cholera pathogen from causing trouble.

    "We think this is going to be a very good vaccine,” said Matthew Waldor, M.D., Ph.D., who is affiliated with both BWH and HHMI, and who is the senior author of the other STM article. “[It] could induce immunity after a single dose."

    In this article, “A Live Vaccine Rapidly Protects against Cholera in an Infant Rabbit Model,” Dr. Waldor and colleagues began with the DNA sequence of the current version of the virulent V. cholerae. Using sophisticated genetic tricks, the researchers tweaked the bacteria's genome, essentially engineering out anything that might make it dangerous. If the bacteria were ever to acquire the DNA sequence for making toxins, for example, a CRISPR-based gene-editing safeguard would chew up that DNA.

    The researchers also hamstrung the bacteria so that they wouldn't be able to swap genes easily and pick up toxic capabilities from other bugs. "We have many different engineering steps to make this an incredibly safe, genetically stable, live vaccine," Waldor added.

    “We demonstrate that administration of HaitiV 24 hours before lethal challenge with wild-type V. cholerae reduced intestinal colonization by the wild-type strain, slowed disease progression, and reduced mortality in an infant rabbit model of cholera,” wrote the article’s authors. “HaitiV-mediated protection required viable vaccine, and rapid protection kinetics are not consistent with development of adaptive immunity. These features suggest that HaitiV mediates probiotic-like protection from cholera, a mechanism that is not known to be elicited by traditional vaccines.”

    Although the two STM articles present early results, they could lead to new strategies for curbing the spread and severity of cholera, one of the world’s most common and devastating infectious diseases. Despite the development of effective rehydration therapies and oral vaccines, cholera still runs rampant in many areas of the developing world such as Haiti and Yemen due to a lack of infrastructure and water sanitation. Current vaccines against cholera can take weeks to induce immunity, which limits the effectiveness of vaccination campaigns during cholera epidemics that often explode within several days.

    Collins says he anticipates that the probiotic, which could be incorporated into a pill or a yogurt-like drink, could be used either as a preventative measure or for treating infections once they begin. Having the ability to diagnose cholera easily could also help public health officials detect outbreaks earlier and monitor the spread of the disease.

    The BWH/HHMI team indicates that an early clinical trial in people is in the works. Waldor and his colleagues are also focused on practical improvements to the vaccine, such as making it stable in environments where cholera is present. The researchers are combing through the genes of V. cholerae, searching for spots that could be altered to promote a longer vaccine shelf life.

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