Digestive distress has dominated recent headlines, as a parasite-driven cyclosporiasis outbreak continues to sicken thousands in North America. But recent research brings brighter news: Researchers have identified a vaccine that provides a high level of protection against shigellosis, a common and potentially deadly form of bacterial diarrhea. The clinical trial, which was published June 30 in The Lancet Infectious Diseases, describes how the oral vaccine could offer a desperately needed defense against bacterial diarrhea.
Scientists Respond to Need for Bacterial Diarrhea Vaccine
While cyclosporiasis is caused by a parasitic infection, shigellosis is a bacterial diarrhea caused by Shigella bacteria. The bacteria can spread through contaminated food, water, or surfaces, as well as via sexual contact. Shigella is a serious public health concern, causing at least 80 million infections around the world each year and leading to as many as 200,000 annual deaths, mostly in low- and middle-income countries. The illness can be especially dangerous for children under the age of five.
However, as the researchers note in the June 30 Lancet publication, no licensed vaccine currently exists for Shigella. To identify existing vaccine candidates, the research team searched PubMed for published clinical trials related to a potential Shigella vaccine. The researchers note in the June 30 article that they “prioritised randomised trials, field efficacy studies, and controlled human infection model studies.”
The search led the team to several Shigella vaccine candidates: Shigella sonnei O-specific polysaccharide bound to Pseudomonas aeruginosa recombinant exoprotein A (S sonnei-rEPA) is one example; the Flexyn2a bioconjugate vaccine candidate is another. Finally, the team honed in on one candidate that had previously shown “safety and immunogenicity”: WRSs2, a live-attenuated vaccine candidate that contains a weakened strain of the Shigella species S. sonnei.
“High-Level Protection” Against Bacterial Diarrhea
A single dose of WRSs2 had previously been tested and deemed safe during a dose-escalating Phase 1 trial in healthy adults, which the team cited in the June 30 article. To build on this, the team organized a small clinical trial to test the efficacy of two oral doses of WRSs2.
The team enrolled 108 adults in the United States between the ages of 18 and 49, each of whom demonstrated little preexisting immunity to S. sonnei. The researchers originally used a three-arm study design that, per the abstract, “allocated participants 1:1:1 to two-dose WRSs2, one-dose placebo followed by one-dose WRSs2, or two-dose placebo.” However, after 69 participants were enrolled, a safety review resulted in the remaining 39 participants being assigned 2:1, either to two-dose WRSs2 or two-dose placebo. In all cases, doses were given 28 days apart.
The scientists then tested the vaccine’s effectiveness in an inpatient setting. All participants received a full-strength oral dose of roughly 1,500 S. sonnei bacteria meant to test the vaccine.
In the study interpretation, the scientists noted that the vaccine provided “high-level protection.” Of the 26 participants who received the placebo, 21 developed shigellosis, representing about 81% of participants. However, of the 34 participants who received two doses of the WRSs2 vaccine, only three developed shigellosis, representing about 8% of participants. Just one of the vaccinated participants developed severe shigellosis symptoms, while 18 of the placebo recipients had similar symptoms.
Next Steps for Vaccine Development
As mentioned above, there is currently no approved vaccine to treat bacterial diarrhea caused by Shigella. The bacterium causes an estimated 450,000 infections each year, with about 242,000 of those classified as drug-resistant. An approved vaccine could minimize the number of resistant infections, greatly reducing the associated treatment costs and the burden on the healthcare system.
Of course, WRSs2 is years away from being approved by vaccine regulatory authorities. A larger clinical trial will likely take years to complete, during which time vaccine dosing must be perfected to reduce potential adverse reactions in patients. Other vaccine candidates, including an intramuscular vaccine that reported a 30% reduction in shigellosis, could take priority.
Finally, the vaccine must be deemed safe and effective in treating the individuals who face the greatest disease burden from shigellosis: young children. To best serve this population, future research will need to rely on the efficient recruitment of diverse, vaccine-naive populations.
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Though WRSs2 may not be an immediate answer to shigellosis, the study is a step in the right direction. “This study represents an important step forward in developing a safe and effective vaccine against Shigella,” said Robert Frenck, the director of the Cincinnati Children’s Vaccine Research Center and joint senior author of the paper. “With continued research, we have the potential to significantly reduce the global burden of this disease, particularly among children.”
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