ObjectivesTyphoid remains a persistent contributor to childhood morbidity in communities lacking sanitation infrastructure. Typhoid conjugate vaccine (TCV) is effective in reducing disease risk in vaccinees, but the duration of protection is unknown. This study measured the longevity of immune response to TCV in children under 10 years in Hyderabad, Pakistan where an outbreak of extensively drug resistant (XDR) typhoid has been ongoing. MethodsA subset of children who received the TCV as part of the outbreak response were enrolled purposively from March 2018-February 2019. The participants were followed until January 2023. Blood samples were taken at baseline, 4-6 weeks, 6 months, and annually 1-4 years post-vaccination to measure anti-Vi-IgG levels using ELISA. Active phone-based surveillance was performed to identify breakthrough infections. Blood culture was offered to any child with a history of fever ≥3 days within the last 7 days. 81 children received a second dose of TCV in November 2019 during a catch-up campaign organized by Sindh government. ResultsNearly all participants seroconverted (802/837; 95·8 %) at 4-6 weeks following vaccination. Four years after vaccination, 438/579 (75·6%) participants remained above the seroconversion threshold. The geometric mean titer (GMT, U/ml) of anti-Vi-IgG at 4-6 weeks was 832·6 (95% CI: 768·0, 902·6); at 4 years post-vaccination, the GMTs in children 6 months-2 years (12·6, {95% CI: 9·8, 16·3}), and >2 - 5 years (40·1, {95% CI: 34·4, 46·6}) were lower than in children >5-10 years (71·1, {95% CI: 59·5, 85·0}). During 4 years of follow-up, 9 children had culture-confirmed S. Typhi infection, these infections occurred after a median duration of 3·4 years. All enteric fever cases seroconverted at 4-6 weeks post-vaccination and 7 (70·0%) remained seroconverted four years post-vaccination. ConclusionWe observed 95·8% seroconversion following a single dose of TCV. There was decay in anti-Vi-IgG titers, and at four years approximately 75·6% remained seroconverted. There was a faster decay in children ≤2 years. Breakthrough infections were documented after a median 3·4 years following vaccination.