A live-attenuated oral vaccine against Shigella sonnei protected 91% of vaccinated adults in a Phase 2b challenge trial, researchers reported this week in The Lancet Infectious Diseases. The result is the highest efficacy ever recorded for a Shigella vaccine candidate, and it renews hope for controlling a disease that sickens at least 80 million people globally each year.
But the efficacy figure, while striking, captures only part of the story. The vaccine’s real test, whether it protects children in low- and middle-income countries, where Shigella kills more people under five than almost any other pathogen, has not yet begun.
The challenge of oral vaccination
The vaccine, designated WRSs2, is a carefully weakened strain of Shigella sonnei administered by mouth. Oral vaccination is the preferred route for enteric diseases because it mimics natural infection, stimulating immune responses in the gut mucosa where the pathogen attacks. But the gut is a hostile environment for a vaccine. Stomach acid, digestive enzymes, and the sheer volume of competing microbiota make it difficult for a live attenuated organism to survive long enough to trigger protective immunity.
The research team, led by Dr. Nadine Rouphael at Emory University, addressed this by halving the dose used in earlier Phase 1 studies. Each dose contained 500,000 weakened S. sonnei bacteria, delivered 28 days apart. A total of 108 healthy US adults aged 18 to 49 with low preexisting immunity were enrolled in the double-blind, placebo-controlled trial.
Approximately one month after the second dose, participants were admitted to a controlled inpatient facility and received a full-strength oral challenge of approximately 1,500 live S. sonnei bacteria, enough to cause disease in most unvaccinated people. The results were dramatic: 3 of 34 vaccinated participants developed shigellosis (8.8%), compared to 21 of 26 in the placebo group (80.8%). Severe symptoms, high fever, excessive diarrhea, occurred in 1 of 34 vaccinated participants (2.9%) versus 18 of 26 in the placebo group (69.2%).
“The protection is higher than what has generally been reported for prior Shigella vaccine studies,” Rouphael told Science News.
Why Shigella matters
Shigellosis causes inflammatory diarrhea, fever, and abdominal cramps. In children under five in endemic regions, it is a leading cause of death from diarrheal disease. It also fuels antibiotic resistance: approximately 54% of the 450,000 annual US infections are drug-resistant, and globally the proportion is even higher. No licensed vaccine currently exists.
The dominant species differs by region. S. sonnei causes the majority of infections in high-income countries, while S. flexneri dominates in lower-income settings where the disease burden is highest. The WRSs2 vaccine targets S. sonnei specifically, which means its efficacy against the globally more prevalent species remains unknown.
The gap between efficacy and effectiveness
David Sack, an epidemiologist at the Johns Hopkins Bloomberg School of Public Health who co-developed an injectable Shigella vaccine with roughly 30% efficacy, pointed out that the dose may need adjustment for different populations. “Finding the right oral dose for the general population might be difficult, as different groups could react differently,” he said.
Children in endemic regions have different gut microbiomes, different nutritional status, and different prior exposure to Shigella and related bacteria than healthy US adults. An oral vaccine that works in Atlanta may produce weaker responses in Dhaka or Nairobi. The WRSs2 team has not yet tested the vaccine in children or in endemic populations.
Shangxin Yang, a molecular microbiologist at UCLA, noted that the regulatory pathway is long: “These are highly encouraging results, but there is a long way from being approved. A big clinical trial would take three to six years to complete.”
The oral advantage
Despite the challenges, oral vaccination remains an attractive approach for Shigella. An injectable vaccine requires trained personnel, sterile equipment, and cold chain logistics. An oral vaccine can be administered by community health workers with minimal training and is easier to deploy in outbreak settings where health infrastructure is damaged.
Other candidates are in development, including the injectable GMMA (Generalized Modules for Membrane Antigens) vaccine that showed promise in a 2023 npj Vaccines study. But the WRSs2 result is the strongest efficacy signal yet from any Shigella vaccine candidate, regardless of delivery route.
What comes next
The research team plans to continue testing WRSs2, with the goal of eventually launching trials in children in Shigella-endemic regions. The vaccine was already shown to be safe and well tolerated in Phase 1 studies. The Phase 2b challenge design, in which participants are deliberately infected under controlled conditions, is standard for enteric vaccine development but cannot substitute for field trials where exposure is natural and ongoing.
For now, the 91% efficacy figure provides a proof of principle: the gut can be vaccinated against Shigella with a live oral vaccine, and the protection can be substantial. The next few years will determine whether that principle can be translated into a practical tool for the children who need it most.
Reference: Rouphael, N. et al. The Lancet Infectious Diseases (2026). DOI: 10.1016/S1473-3099(26)00224-000224-0)