The Lancet. Global health · 2027
8-year vaccine protection following a single dose of Vi-tetanus toxoid conjugate vaccine in children in Nepal (TyVOID): a prospective cohort follow-up study of the TyVAC Nepal randomised controlled trial.
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Pant Dikshya, Zhang Yiyuan, Basile Francesca W, Shakya Mila, Kelly Sarah, Gurung Meeru, Subhani Huma, Shrestha Suchita, Mujadidi Yama F, Dongol Sabina, Haque Naheeda, Joshi Manij, Maharjan Archana, Dahal Ashata, Karkey Abhilasha, Rijal Suraj, Rajkarnikar Shristy, Nepal Jita, Ghimire Sushan, Curtis Benjamin, Kim Young Chan, Voysey Merryn, Basnyat Buddha, Shrestha Shrijana, Pollard Andrew J, Liu Xinxue, TyVAC/TyVOID Nepal study team
Аннотация
BACKGROUND: In low-income and middle-income countries, where typhoid fever remains a major public health problem, WHO recommends the use of typhoid conjugate vaccine (TCV). Here, we report vaccine effectiveness up to 8 years following a single dose of TCV in Nepal.
METHODS: TyVOID was a prospective cohort study that extended the follow-up of children enrolled in a phase 3, double-blind, randomised controlled trial in Lalitpur, Nepal (TyVAC; Nov 20, 2017, to Oct 20, 2021). Children aged 9 months to 15 years were randomly assigned (1:1) to receive Vi-tetanus toxoid conjugate vaccine (Vi-TT) or a capsular group A meningococcal conjugate (MenA) vaccine. After unmasking and crossover vaccination, our study followed the trial participants until Oct 31, 2025. TyVAC participants who received Vi-TT were eligible for this study and categorised into either the 2017-18 cohort or 2020-21 cohort, depending on when they received the Vi-TT vaccine. The primary outcome, which was assessed in children who received both Vi-TT and MenA vaccines and with known TCV vaccination status during the government catch-up campaign in 2022, 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 1-5 years and 4-8 years post-vaccination was estimated using a test-negative design among febrile children presenting to surveillance clinics, comparing odds of Vi-TT vaccination between culture-confirmed typhoid cases with negative controls.
FINDINGS: 16 131 TyVAC participants were enrolled at TyVOID baseline, of whom 14 850 provided information on Vi-CRM197 vaccination during the government catch-up campaign. After crossover and unmasking, the primary analysis population included 4941 participants vaccinated with Vi-TT in 2017-18 and 4856 participants vaccinated with Vi-TT in 2020-21. In 4856 participants in the 2020-21 Vi-TT cohort, 2402 (49·5%) were female, 2454 (50·5%) were male, and the median age at Vi-TT vaccination was 10·4 years (IQR 7·3-13·7). In 4941 participants in the 2017-18 Vi-TT cohort, 2482 (50·2%) were female, 2459 (49·8%) were male, and the median age at Vi-TT vaccination was 7·7 years (IQR 4·5-11·0). During a median follow-up of 3·7 years (3·7-3·8), the typhoid incidence rate was 111 per 100 000 person-years (95% CI 64-177) in the 2017-18 cohort and 46 per 100 000 person-years (18-94) in the 2020-21 cohort (adjusted IRR 2·41 [95% CI 1·00-5·80]; one-sided p=0·025). Vaccine effectiveness was 77% (95% CI 46-90; p=0·0006) in the 2020-21 Vi-TT cohort (1-5 years after vaccination), and 53% (8-76; p=0·027) in the 2017-18 Vi-TT cohort (4-8 years after vaccination).
INTERPRETATION: A single Vi-TT dose confers strong protection in the first 4 years among Nepali children, with evidence of waning by 8 years. These findings support consideration of a booster dose to sustain protection in school-age children who remain at high risk of typhoid fever.
FUNDING: Gates Foundation and Wellcome Trust.
METHODS: TyVOID was a prospective cohort study that extended the follow-up of children enrolled in a phase 3, double-blind, randomised controlled trial in Lalitpur, Nepal (TyVAC; Nov 20, 2017, to Oct 20, 2021). Children aged 9 months to 15 years were randomly assigned (1:1) to receive Vi-tetanus toxoid conjugate vaccine (Vi-TT) or a capsular group A meningococcal conjugate (MenA) vaccine. After unmasking and crossover vaccination, our study followed the trial participants until Oct 31, 2025. TyVAC participants who received Vi-TT were eligible for this study and categorised into either the 2017-18 cohort or 2020-21 cohort, depending on when they received the Vi-TT vaccine. The primary outcome, which was assessed in children who received both Vi-TT and MenA vaccines and with known TCV vaccination status during the government catch-up campaign in 2022, 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 1-5 years and 4-8 years post-vaccination was estimated using a test-negative design among febrile children presenting to surveillance clinics, comparing odds of Vi-TT vaccination between culture-confirmed typhoid cases with negative controls.
FINDINGS: 16 131 TyVAC participants were enrolled at TyVOID baseline, of whom 14 850 provided information on Vi-CRM197 vaccination during the government catch-up campaign. After crossover and unmasking, the primary analysis population included 4941 participants vaccinated with Vi-TT in 2017-18 and 4856 participants vaccinated with Vi-TT in 2020-21. In 4856 participants in the 2020-21 Vi-TT cohort, 2402 (49·5%) were female, 2454 (50·5%) were male, and the median age at Vi-TT vaccination was 10·4 years (IQR 7·3-13·7). In 4941 participants in the 2017-18 Vi-TT cohort, 2482 (50·2%) were female, 2459 (49·8%) were male, and the median age at Vi-TT vaccination was 7·7 years (IQR 4·5-11·0). During a median follow-up of 3·7 years (3·7-3·8), the typhoid incidence rate was 111 per 100 000 person-years (95% CI 64-177) in the 2017-18 cohort and 46 per 100 000 person-years (18-94) in the 2020-21 cohort (adjusted IRR 2·41 [95% CI 1·00-5·80]; one-sided p=0·025). Vaccine effectiveness was 77% (95% CI 46-90; p=0·0006) in the 2020-21 Vi-TT cohort (1-5 years after vaccination), and 53% (8-76; p=0·027) in the 2017-18 Vi-TT cohort (4-8 years after vaccination).
INTERPRETATION: A single Vi-TT dose confers strong protection in the first 4 years among Nepali children, with evidence of waning by 8 years. These findings support consideration of a booster dose to sustain protection in school-age children who remain at high risk of typhoid fever.
FUNDING: Gates Foundation and Wellcome Trust.