A two-dose, live-attenuated oral vaccine candidate called WRSs2 reduced the risk of shigellosis among healthy adults deliberately exposed to Shigella sonnei in a US study. Among challenged participants, shigellosis occurred in 9% of those who received two vaccine doses compared with 81% of placebo recipients, corresponding to vaccine efficacy of 89% (95% CI, 71%-96%; P<.0001).
The phase 2, double-blind, randomized, placebo-controlled trial was conducted at Cincinnati Children's Hospital Medical Center and the Hope Clinic of the Emory Vaccine Center. The results were published in The Lancet Infectious Diseases.
“The main new insight is that an oral, live-attenuated Shigella sonnei vaccine can provide a high level of protection in a rigorous, randomized controlled human infection study,” said first author Nadine Rouphael, MD, MSc, professor at the Hope Clinic of the Emory Vaccine Center, Division of Infectious Diseases, Department of Medicine, Emory University, Decatur, Georgia. “The findings also demonstrate the value of controlled human infection models for identifying promising Shigella vaccine candidates before proceeding to larger and more costly field trials," she said in an interview with this news organization.
Dr. Rouphael and colleagues enrolled 108 adults aged 18 to 49 with little existing immunity to S. sonnei. Participants received either two oral vaccine doses, one placebo followed by one vaccine dose, or two placebo doses, given 28 days apart.
After some participants developed grade 3 gastrointestinal side effects, researchers revised the study for safety. They cut the vaccine dose in half, stopped enrolling people in the one-dose group, and excluded those with a body mass index over 40 kg/m² or who were taking weight-loss medications. New participants were twice as likely to receive the lower-dose vaccine as the placebo.
Twenty-eight days after the second scheduled dose, 73 participants were exposed to about 1,500 colony-forming units of S. sonnei. An independent committee that did not know who received the vaccine determined who developed shigellosis based on predefined criteria, including diarrhea, fever, other symptoms, and dysentery.
Among the 34 participants who received two vaccine doses, three developed shigellosis, compared with 21 of the 26 who received a placebo. The results remained the same when researchers included only participants who followed the study protocol.
In additional analyses, three of 16 participants who received two higher-dose vaccines became ill. No cases occurred among the 18 who received two lower doses or the 13 who received one higher dose. However, the groups were too small to draw firm conclusions, and the study was not designed to formally compare them.
Severe shigellosis occurred in 3% of participants who received two vaccine doses, compared with 69% of those given a placebo. In a post-hoc analysis, vaccine efficacy against severe shigellosis was 96%. Vaccinated participants were less likely to shed bacteria after challenge than placebo recipients, 53% versus 88%, and peak stool bacterial loads were approximately one log, or about 11-fold, lower. The study did not determine whether vaccination reduced transmission.
Side effects were common in both groups. Among vaccine recipients, the most common were headache (59%), fatigue or generally feeling unwell (53%), diarrhea (45%), and stomach pain or cramping (36%). Six of 108 participants (6%) had grade 3 post-vaccination adverse events, prompting two Data and Safety Monitoring Board reviews. The events included gastrointestinal symptoms and fever; two later events occurred with inter-current SARS-CoV-2 or norovirus infection and were considered probably unrelated to vaccination. The remaining two later events involved self-limited severe diarrhea. No vaccine-related or challenge-related serious adverse events or deaths occurred.
The findings do not support clinical use because WRSs2 remains investigational, noted investigators. Limitations included the small sample, protocol changes, healthy adult population, challenge 28 days after vaccination and lack of data from children or endemic settings.
According to Dr. Rouphael, further research is needed to determine the optimal vaccine dose and dosing schedule, assess the duration of protection, establish immune correlates of protection, and further improve the vaccine’s safety and tolerability. “The most important next step is to conduct larger field trials in the populations who bear the greatest burden of disease, particularly young children living in endemic settings,” she said.
Expert Insights
Dr. Rouphael shared additional insights on the study findings with this news organization.
Were there any findings that you didn’t anticipate when you saw the final results?
Dr. Rouphael: The magnitude of protection was the most striking finding. We were also encouraged that none of the 13 challenged participants who received a single dose developed shigellosis. However, that group was small, so the result should not be interpreted as establishing that one dose is sufficient.
At the same time, the occurrence of a few self-limited grade 3 adverse events was an important reminder that, with a live oral vaccine, we must carefully optimize the dose and regimen to achieve the best balance between protection and tolerability. It was reassuring that no vaccine-related serious adverse events or deaths occurred.
How might the findings influence clinical practice?
Dr. Rouphael: These findings should not change clinical practice today because WRSs2 remains investigational, and there is currently no licensed Shigella vaccine. Their immediate importance is for vaccine development: the results provide a strong rationale for advancing this candidate into field trials.
Should its efficacy and safety be confirmed in larger studies, a Shigella vaccine could ultimately be particularly important for young children in endemic settings and potentially for travelers, military personnel, and populations affected by outbreaks.
What gaps remain, and what research should be done next?
Dr. Rouphael: This study evaluated healthy US adults challenged with a single S. sonnei strain. We therefore also need to determine how well the vaccine performs under conditions of natural exposure and how it could contribute to a broader vaccine strategy that protects against other important Shigella species and serotypes, particularly S. flexneri. It will also be valuable to determine whether the lower bacterial shedding observed after challenge translates into reduced transmission.
Is there anything else you’d like to say about this work?
Dr. Rouphael: This is a meaningful step forward, but it is not the finish line. Controlled human infection models can accelerate vaccine development and provide an early, rigorous assessment of efficacy, but they do not replace the need for robust safety and effectiveness data in the real-world populations for whom the vaccine is ultimately intended.
