BackgroundSalmonella Typhi is a major cause of fever in children in low- and middle-income countries. The recently WHO prequalified typhoid conjugate vaccine (TCV) was shown to be efficacious in a human challenge model but no efficacy trials in endemic populations have been completed.MethodsIn this phase III participant- and observer-blinded randomized controlled trial in Lalitpur, Nepal, children aged 9 months to <16 years of age, were randomized 1:1 to receive either TCV or a capsular group A meningococcal conjugate vaccine (Men A) as control. The primary endpoint was blood culture-confirmed typhoid fever. Study follow-up continues for 2 years; here we present the interim analysis after 12 months of follow-up, for safety, immunogenicity and efficacy.Results10,005 participants received TCV and 10,014 received Men A. Blood culture-confirmed typhoid fever occurred in 7 participants who received TCV and 38 receiving Men A; vaccine efficacy: 81.6% (95% CI, 58.8%, 91.8%, P<0.001). 132 SAEs occurred in the first 6 months with one (pyrexia) identified as vaccine-related. The participant remains blinded. Seroconversion (≥ four-fold rise in Vi-IgG 28 days after vaccination) was 99% in the TCV group (N=677/683) and 2% in the control group (N=8/380).ConclusionA single dose of TCV is safe, immunogenic, and effective, and the deployment of the vaccine will reduce the burden of typhoid in high-risk populations. This new evidence of efficacy is especially timely with the recent spread of extensively drug resistant typhoid fever which threatens child health in affected regions.Trial registration numberISRCTN43385161

Background Typhoid fever is a major public health problem in low-resource settings. Vaccination can help curb the disease and might reduce transmission. We have previously reported an interim analysis of the efficacy of typhoid conjugate vaccine (TCV) in Nepali children. Here we report the final results after 2 years of follow-up. MethodsWe did a participant-masked and observer-masked individually randomised trial in Lalitpur, Nepal, in which 20 019 children aged 9 months to younger than 16 years were randomly assigned in a 1:1 ratio to receive a single dose of TCV (Typbar TCV, Bharat Biotech International, India) or capsular group A meningococcal conjugate vaccine (MenA). Participants were followed up until April 9, 2020. The primary outcome was blood culture-confirmed typhoid fever. Cases were captured via passive surveillance and active telephone surveillance followed by medical record review. The trial is registered at ISRCTN registry, ISRCTN43385161 and is ongoing.