Oral Salmonella Paratyphi A Vaccine Demonstrates 73% Efficacy in First Human Challenge Trial
Key Insights
An oral live-attenuated vaccine CVD 1902 showed 73% efficacy against Salmonella Paratyphi A infection in a phase 2b human challenge trial involving 72 healthy UK adults.
The vaccine represents the first modern-day vaccine proven to protect against S. Paratyphi A, which causes more than 2 million cases of enteric fever (search) annually with no currently available vaccine.
The double-blind, randomized trial found only 21% of vaccinated participants developed infection compared to 75% in the placebo group following deliberate exposure to the pathogen.
Scientists in the United Kingdom have achieved a significant breakthrough in infectious disease prevention, demonstrating that an investigational oral vaccine provides substantial protection against Salmonella enterica serovar Paratyphi A (search), a pathogen that causes more than 2 million cases of enteric fever (search) annually worldwide. The phase 2b human challenge trial, published in the New England Journal of Medicine, showed the vaccine CVD 1902 reduced infection risk by 73% compared to placebo.
First Vaccine to Show Protection Against S. Paratyphi A
The oral live-attenuated vaccine CVD 1902, developed at the University of Maryland, targets antigens most likely to produce an immune response to S. Paratyphi A, which spreads through contaminated food and water. Currently, no vaccine is available for this strain of Salmonella, making this development particularly significant for global health.
"This is the first time a modern-day vaccine has been shown to protect people against Salmonella Paratyphi A, a disease that affects millions of people every year," said lead study author Naina McCann, PhD, a clinical research fellow at the Oxford Vaccine Group (search). "By using a controlled human infection model, we were able to show that this vaccine was effective using only a small number of participants, greatly accelerating the path to a licensed vaccine."
Trial Design and Results
The double-blind, randomized trial enrolled 72 healthy participants aged 18 to 55 at six UK sites from April 2022 through November 2023. Participants were randomly assigned to receive two doses of CVD 1902 or placebo administered 14 days apart. Four weeks after the second dose, all participants were deliberately challenged orally with a wild-type strain of S. Paratyphi A isolated in 2006 from a patient in Nepal.
The primary endpoint was diagnosis of S. Paratyphi A infection within 14 days of the challenge. In the intention-to-treat population, infection was diagnosed in 7 (21%) of 34 participants in the CVD 1902 group compared to 27 (75%) of 36 participants in the placebo group, resulting in a vaccine efficacy of 73% (95% CI, 46–86%). The per-protocol analysis confirmed these results with 69% efficacy (95% CI, 42–84%).
Safety and Immunogenicity Profile
The vaccine demonstrated a favorable safety profile, with the number of adverse events similar between vaccine and placebo groups. Nausea and vomiting were more commonly reported in the vaccine group, but no serious vaccine-related adverse events were identified. All study participants received antibiotic treatment for 7 to 14 days following the challenge.
Immunogenicity results showed CVD 1902 induced significant serum IgG and IgA antibody responses to the S. Paratyphi A O lipopolysaccharide (search) antigen but not the FliC (search) (flagellin) antigen. No increases in serum antibody titers occurred in the placebo group.
Path to Implementation
The World Health Organization has endorsed the use of human challenge trials to support licensure of S. Paratyphi A vaccines due to the difficulty of conducting field trials, which would require large numbers of participants given the relatively low incidence of paratyphoid fever (search). However, the researchers note that the vaccine ultimately needs field-testing in its target population—school-aged children in endemic areas, primarily in Asia and Africa.
"We are in a constant fight against bacterial infections, like paratyphoid, that threaten the lives of children in some of the most resource-poor regions of the world," said study co-senior author and Oxford Vaccine Group (search) director Sir Andrew Pollard, MBBS, PhD. "This study provides hope that this important disease could be controlled by vaccination if the same effects can be obtained in real-life conditions in those communities."
Future Development Strategy
The researchers are also evaluating bivalent vaccines that would target both S. Paratyphi A and S. Typhi, the other leading cause of enteric fever (search). "A bivalent vaccine targeting S. Paratyphi A and S. Typhi is the most likely path to licensure for an S. Paratyphi A vaccine because such a vaccine offers a comprehensive approach to preventing enteric fever," the authors wrote.
This development represents a critical advancement in addressing a major unmet need in global health, potentially providing a practical, effective tool to prevent enteric fever (search) in endemic regions where millions remain at risk.