Eight-Year Vaccine Protection Following a Single Dose of VI-Tetanus Toxoid Conjugate Vaccine in Nepali Children: Extended Follow-Up of the TyVAC Nepal Randomised Controlled Trial

Background: Typhoid remains a major public health problem in low- and middle-income countries, including Nepal, and WHO recommends typhoid conjugate vaccines in high-burden settings. We report vaccine effectiveness up to eight years following a single dose of typhoid conjugate vaccine (TCV).&nbsp; <div> <br> </div> <div> Methods: TyVOID is a prospective cohort study extending follow-up of children enrolled in a phase 3, double-blind, randomised trial in Lalitpur, Nepal (TyVAC, Nov 2017–Oct 2021). Children aged 9 months to younger than 16 years were randomly assigned (1:1) to receive Vi-TT or a capsular group A meningococcal conjugate vaccine. After unmasking (2020-21) and cross-over vaccination, our study followed the trial participants till October 2025. Children who received Vi-TT were classified as previous (2017-18) or recent (2020-21) vaccinees. The primary outcome was the incidence of blood culture-confirmed typhoid identified through facility-based passive surveillance and medical record review. Adjusted incidence rate ratios (IRRs) were estimated using Poisson regression adjusted for age and sex. Vaccine effectiveness at one to five years and four to eight years post-vaccination was estimated using a test-negative design among febrile children presenting to surveillance clinics (2021-25), comparing odds of Vi-TT vaccination between culture-confirmed typhoid cases with negative controls.&nbsp; </div> <div> <br> </div> <div> Findings: 12,236 TyVAC participants were included. The primary analysis population included 4,941 previous and 4,856 recent Vi-TT vaccinees who attended the final trial visit. During a median follow-up of 3.7 years, typhoid incidence was 111 per 100,000 PYs (95% CI 64–177) among previous and 46 (18–94) among recent vaccinees (adjusted IRR 2.41, 95% CI 1.00–5.80). Vaccine effectiveness was 77% at one to five years (95% CI 46–90; p=0.0006) and 53% at four to eight years (8–76; p=0.0267).&nbsp; </div> <div> <br> </div> <div> Interpretation: A single Vi-TT dose confers strong protection in the first four years among Nepali children, with evidence of waning by eight years. These findings support consideration of a booster dose to sustain protection in children at school age when typhoid risk remains high.&nbsp;FundingTyVAC- Gates Foundation (grant number OPP1151153); TyVOID- Wellcome Trust (projects number 221438/Z/20/Z; 221348/Z/20/Z). </div>