An Oral Vaccine Against Salmonella Paratyphi A Shows Promise
December 1, 2025
By Jake Scott, MD
Synopsis: In a Phase IIb controlled human infection model study, the oral live attenuated vaccine CVD 1902 demonstrated 73% efficacy against Salmonella Paratyphi A infection, with a favorable safety profile and robust immunogenicity, supporting advancement toward field trials in endemic populations.
Source: McCann N, Paganotti Vicentine M, Ebrahimi N, et al. Safety, efficacy, and immunogenicity of a Salmonella Paratyphi A vaccine. N Engl J Med. 2025;393(17):1704-1714.
Enteric fever caused by Salmonella enterica serovar Paratyphi A causes more than 2 million cases annually, representing up to 30% of all enteric fever cases globally, yet no licensed vaccines exist against this pathogen.1 McCann and colleagues conducted a double-blind, randomized, placebo-controlled trial across six United Kingdom research centers to evaluate CVD 1902, an oral live attenuated vaccine candidate engineered by deleting the guaBA operon and clpX gene from wild-type S. Paratyphi A.1
The study enrolled 72 healthy adults aged 18-55 years with no history of enteric fever. Following 1:1 randomization, participants received two oral doses of CVD 1902 (minimum 2 × 1010 colony-forming units [CFUs]) or placebo 14 days apart. Twenty-eight days after the second dose, participants underwent controlled oral challenge with 1 × 103 to 5 × 103 CFUs of wild-type S. Paratyphi A strain NVGH308.
The primary endpoint was diagnosis of S. Paratyphi A infection within 14 days after challenge, defined as either a positive blood culture obtained more than 72 hours post-challenge or fever (≥ 38°C) persisting for at least 12 hours. Of 70 participants who completed vaccination and challenge (34 vaccine, 36 placebo), infection occurred in 21% (7/34) of vaccine recipients vs. 75% (27/36) of placebo recipients (P < 0.001), yielding vaccine efficacy of 73% (95% confidence interval [CI], 46% to 86%).
The vaccine was generally well-tolerated. Nausea/vomiting (17% vs. 0%) and feeling generally unwell (34% vs. 8%) occurred more frequently after the first vaccine dose compared to placebo, with most symptoms mild to moderate. Four serious adverse events occurred (two per group); none were assessed as vaccine-related.
CVD 1902 induced significant serum immunoglobulin G (IgG) and immunoglobulin A (IgA) responses to S. Paratyphi A O antigen. Geometric mean anti-O IgG titers increased 2.5-fold from baseline (126 EU/mL) to day 14 post-first dose (314 EU/mL). Interestingly, pre-challenge antibody levels did not clearly correlate with protection, although higher anti-O IgA titers showed a trend toward protection, suggesting mucosal or cell-mediated immunity may be critical.
Among infected participants, only 29% of vaccine recipients and 19% of placebo recipients developed fever, highlighting that S. Paratyphi A causes a spectrum of disease, including afebrile bacteremia. The vaccine demonstrated potential transmission-blocking effects, with positive stool cultures occurring in 24% of vaccine recipients vs. 50% of placebo recipients.
Commentary
This study represents a critical advance in S. Paratyphi A vaccine development. The 73% efficacy exceeds that of licensed S. Typhi vaccines tested in similar controlled human infection models, including Ty21a (35%) and Vi-tetanus toxoid conjugate (54.6%).2 The controlled human infection model approach, endorsed by the World Health Organization (WHO) for S. Paratyphi A vaccine development given the impracticality of large field trials, provides valuable efficacy data while minimizing participant exposure.3
Several limitations warrant consideration. The study population of healthy U.K. adults (71% white British) differs substantially from the target population of children in South Asian endemic areas where incidence peaks at ages 5-9 years.4 The controlled challenge used lower inoculum (103 to 104 CFUs) than the S. Typhi model (104 to 105 CFUs) and natural exposure, potentially affecting efficacy estimates. The current formulation requires same-day preparation, necessitating development of a thermostable version for field deployment.
The absence of antibody correlates of protection complicates vaccine evaluation but aligns with observations from other live oral vaccines.5 The trend toward protection with higher anti-O IgA titers suggests mucosal immunity’s importance, consistent with the vaccine’s oral route. Future studies should evaluate mucosal antibody responses and cell-mediated immunity.
Three participants experienced bacteremia relapse (all placebo group), including one with two relapse episodes, highlighting S. Paratyphi A’s propensity for recurrence. The protocol’s antibiotic duration was extended from seven to 14 days mid-study due to persistent stool shedding, underscoring the organism’s persistence.
The path forward likely involves combining S. Paratyphi A and S. Typhi protection in a bivalent vaccine for comprehensive enteric fever prevention. Several bivalent conjugate vaccines are in development, although none have undergone efficacy assessment. Given that S. Paratyphi A causes up to 30% of enteric fever cases globally, with > 80% concentrated in South Asia, and rising antimicrobial resistance (14% ciprofloxacin nonsusceptibility in the European Union), vaccine development is urgent.
CVD 1902’s favorable safety profile, robust efficacy, and potential transmission-blocking effects support advancement to field trials in endemic populations. As antimicrobial resistance complicates enteric fever management, this vaccine candidate represents a critical tool for disease control.
Jake Scott, MD, is Associate Clinical Professor of Medicine, Stanford University.
References
1. McCann N, Paganotti Vicentine M, Ebrahimi N, et al. Safety, efficacy, and immunogenicity of a Salmonella Paratyphi A vaccine. N Engl J Med. 2025;393(17):1704-1714.
2. Darton TC, Jones C, Blohmke CJ, et al. Using a human challenge model of infection to measure vaccine efficacy: A randomised, controlled trial comparing the typhoid vaccines M01ZH09 with placebo and Ty21a. PLoS Negl Trop Dis. 2016;10(8):e0004926.
3. World Health Organization. Typhoid vaccines: WHO position paper, March 2018 — Recommendations. Vaccine. 2019;37(2):214-216.
4. GBD 2017 Typhoid and Paratyphoid Collaborators. The global burden of typhoid and paratyphoid fevers: A systematic analysis for the Global Burden of Disease Study 2017. Lancet Infect Dis. 2019;19(4):369-381.
5. Jin C, Hill J, Gunn BM, et al. Vi-specific serological correlates of protection for typhoid fever. J Exp Med. 2021;218(2):e20201116.
In a Phase IIb controlled human infection model study, the oral live attenuated vaccine CVD 1902 demonstrated 73% efficacy against Salmonella Paratyphi A infection, with a favorable safety profile and robust immunogenicity, supporting advancement toward field trials in endemic populations.
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