Oral Shigella Vaccine Candidate WRSs2 Demonstrates 89% Efficacy in Phase 2 Controlled Human Infection Trial
Key Insights
An oral live-attenuated Shigella (search) sonnei vaccine candidate, WRSs2, achieved 89% protection against shigellosis in a phase 2 controlled human infection trial published in The Lancet Infectious Diseases.
Only 3 of 34 vaccinated participants developed shigellosis compared with 21 of 26 placebo recipients, with just 3% experiencing severe symptoms versus 69% in the placebo group.
The trial enrolled 108 healthy adults aged 18–49, and no vaccine-related serious adverse events were reported, supporting a favorable safety profile.
An experimental oral vaccine against Shigella (search) has demonstrated 89% protection in a phase 2 clinical trial, marking what researchers describe as a significant advance in the century-long effort to develop an effective vaccine against the highly contagious diarrheal pathogen. The findings, published online in The Lancet Infectious Diseases, showed that two doses of the live-attenuated candidate WRSs2 substantially exceeded the efficacy reported in prior Shigella vaccine studies.
"This study represents an important step forward in developing a safe and effective vaccine against Shigella (search)," said Robert Frenck, MD, professor in the Division of Infectious Diseases at Cincinnati Children's and director of the Vaccine Research Center, who served as joint senior author. "With continued research, we have the potential to significantly reduce the global burden of this disease, particularly among children."
The Global Burden of Shigellosis
Shigella (search) infects tens of millions of people worldwide each year and causes hundreds of thousands of deaths. Children aged 1 to 5 years account for the majority of cases and are at highest risk of severe illness and death. In the United States alone, an estimated 450,000 Shigella infections occur annually, with over 5,000 hospitalizations and dozens of fatalities. The bacterium spreads through fecal contamination of water or food, as well as through person-to-person contact and sexual transmission.
Compounding the public health threat, Shigella (search) is increasingly difficult to treat due to growing antibiotic resistance. An estimated 242,000 of the 450,000 annual U.S. infections are resistant to at least one antimicrobial drug. Despite more than 100 years of research, no licensed Shigella vaccine currently exists.
Trial Design and Key Findings
The phase 2 trial enrolled 108 healthy adults aged 18 to 49 years between October 11, 2022, and January 9, 2024. Participants had little preexisting immunity to Shigella (search) sonnei, the Shigella species more commonly seen in higher-income countries where outbreaks are linked to international travel, military deployments, and childcare settings.
WRSs2 is a live-attenuated vaccine that uses a weakened form of S. sonnei bacteria to stimulate immune protection without causing full disease. In the trial, a large group of participants received two doses of 500,000 weakened S. sonnei bacteria — half the dose used in earlier studies — administered 28 days apart. Another group received placebo.
Nearly one month after the second dose, researchers tested vaccine effectiveness in a closely monitored inpatient setting using a controlled human infection model. Participants received a live, full-strength oral challenge dose of roughly 1,500 S. sonnei bacteria. The results were striking: only 3 of 34 participants (approximately 9%) who received two vaccine doses developed shigellosis, compared with 21 of 26 placebo recipients (approximately 81%). This translated to 89% vaccine efficacy.
Furthermore, just one vaccinated participant (3%) developed severe shigellosis symptoms such as high fever or excessive diarrhea, while 18 placebo recipients (69%) experienced similar severe symptoms. Vaccinated participants also demonstrated less severe symptoms overall and lower levels of bacterial shedding, suggesting the vaccine may help curb transmission.
"The protection is higher than what has generally been reported for prior Shigella (search) vaccine studies," said study coauthor Nadine Rouphael, a vaccinologist at Emory University.
Safety Profile and Dosing Considerations
No vaccine-related serious adverse events were reported, supporting a favorable safety profile. However, a small number of participants experienced temporary side effects, which led to adjustments in dosing during the trial. Two participants developed symptoms of severe shigellosis and did not continue in the study.
Rouphael noted the inherent challenge in oral vaccine development: the vaccine must "work in the gut, where the infection starts, and it must be strong enough to protect but gentle enough not to cause too many stomach and intestinal symptoms."
Limitations and Next Steps
Researchers acknowledged several important limitations. The vaccine was tested against S. sonnei, the dominant Shigella (search) species in the United States, but globally the predominant species is S. flexneri. Shangxin Yang, a molecular microbiologist at the UCLA School of Medicine who was not involved in the study, noted that because the vaccine was tested on adults and on the less common global species, it remains unclear whether it would work in young children in low- and middle-income countries, who bear the greatest disease burden.
Epidemiologist David Sack of the Johns Hopkins Bloomberg School of Public Health, who was part of a team working on an intramuscular Shigella (search) vaccine that reported a 30% reduction in shigellosis, cautioned that finding the right oral dose for the general population might prove difficult, as different groups could react differently.
The WRSs2 vaccine is not yet commercially manufactured and is being developed through collaborations among government, military, and academic research teams. Funding was provided by the National Institutes of Health with pharmaceutical support from the U.S. Department of Defense (search). Contributing institutions included Emory University, the National Institute of Allergy and Infectious Diseases, the Emmes Company, Walter Reed Army Institute of Research, and the Naval Medical Research Command.
Future research will focus on long-term protection, optimal dosing, broader coverage against multiple Shigella (search) strains, and studies in high-risk populations. Rouphael stated her team plans to test WRSs2 in populations "that need it most, especially young children in places where Shigella is common." Yang estimated that a large confirmatory clinical trial would take three to six years to complete before the vaccine could be considered for regulatory approval.