Efficacy of typhoid conjugate vaccine in Nepal: final results of a phase 3, randomised, controlled trial
Mila Shakya, Merryn Voysey, Katherine Theiss-Nyland, Rachel Colin-Jones, Dikshya Pant, Anup Adhikari, Susan Tonks, Yama F Mujadidi, Peter O'Reilly, Olga Mazur, Sarah Kelly, Xinxue Liu, Archana Maharjan, Ashata Dahal, Naheeda Haque, Anisha Pradhan, Suchita Shrestha, Manij Joshi, Nicola Smith, Jennifer Hill, Jenny Clarke, Lisa Stockdale, Elizabeth Jones, Timothy Lubinda, Binod Bajracharya, Sabina Dongol, Abhilasha Karkey, Stephen Baker, Gordan Dougan, Virginia E Pitzer, Kathleen M Neuzil, Shrijana Shrestha, Buddha Basnyat, Andrew J Pollard, TyVAC Nepal Team
Lancet Global Health · 2021 · DOI: 10.1016/S2214-109X(21)00346-6
Countries: Nepal
What Was Studied
This phase 3, participant- and observer-masked, individually randomised controlled trial enrolled 20,019 children aged 9 months to under 16 years in Lalitpur Metropolitan City, an urban part of Kathmandu Valley, Nepal, between November 2017 and April 2018. Children were randomly assigned 1:1 to a single dose of typhoid conjugate vaccine (TCV; Typbar-TCV, Bharat Biotech) or a control meningococcal A conjugate vaccine (MenA). Blood culture-confirmed typhoid fever, captured through passive surveillance at trial clinics and Patan Hospital plus active tri-monthly telephone follow-up with medical record review, was the primary outcome over a 2-year follow-up period (through April 2020). This paper reports the trial's final 2-year results, following a previously published 1-year interim analysis (NEJM, 2019).
What They Found
Over 2 years, there were 13 blood culture-confirmed typhoid cases in the TCV group versus 62 in the MenA (control) group, giving a vaccine efficacy of 79.0% (95% CI 61.9–88.5; p<0.0001). Typhoid incidence was 72 per 100,000 person-years in the TCV group versus 342 per 100,000 person-years in the MenA group. Efficacy showed no significant waning over time: 83.4% (95% CI 60.5–93.0) in the first 12 months versus 73.0% (95% CI 37.9–88.3) thereafter (p=0.43 for the difference). Anti-Vi IgG seroconversion was 99% at 28 days and remained at 95% at 18 months post-vaccination. TCV showed no efficacy against paratyphoid fever (vaccine efficacy −16.7%, not significant), confirming it does not protect against this related but distinct infection. Among isolates tested, 81% (in the MenA group) to 91% (in the TCV group) were non-susceptible to ciprofloxacin (a fluoroquinolone), though no multidrug-resistant or extensively drug-resistant strains were identified.
What This Means for Nepal
This trial, conducted in Lalitpur, generated the core efficacy evidence behind Nepal's introduction of TCV as the fourth country globally to do so, culminating in the April 2022 national catch-up campaign (>7 million children, >90% coverage) and now-routine dosing at 15 months within the Expanded Programme on Immunization (EPI), which already achieves 89% Penta-3 and measles-1 coverage nationally. Three actions follow directly from these results. First, DoHS's Family Welfare Division should sustain close monitoring of routine 15-month TCV coverage and impact, since post-introduction surveillance has already shown roughly a 75% drop in S. Typhi positivity among vaccine-eligible children — continued tracking will show whether this holds as catch-up-campaign cohorts age out of eligibility. Second, because efficacy in this trial declined only modestly and non-significantly from year 1 (83.4%) to year 2 (73.0%), MoHP should keep tracking medium- to long-term protection to determine if and when a booster dose might be needed. Third, since this trial's antimicrobial-resistance findings — high fluoroquinolone non-susceptibility (81–91%) but no MDR or XDR isolates — mirror Nepal's broader typhoid AMR profile (~86% fluoroquinolone non-susceptibility nationally, with MDR and XDR strains each only ~1%), antibiotic stewardship efforts should prioritise curbing inappropriate fluoroquinolone prescribing rather than over-emphasising an MDR/XDR threat that the data do not currently support. Because TCV does not protect against paratyphoid fever, WASH investment (Nepal has 98% basic water access but only 73% basic sanitation coverage) remains essential alongside vaccination.
Contextualisation
Kathmandu Valley is described as the world's 'enteric fever capital', and this trial was conducted in exactly that setting — Lalitpur — where child typhoid incidence has been measured at 428 per 100,000 person-years and fluoroquinolone non-susceptibility runs at roughly 86% nationally, complicating treatment. This trial's landmark efficacy results directly underpinned Nepal's decision to become the fourth country worldwide to introduce typhoid conjugate vaccine (TCV) into its national immunisation programme, culminating in an April 2022 catch-up campaign that reached over 7 million children at above 90% coverage, with TCV now delivered routinely at 15 months through the Expanded Programme on Immunization (EPI) — one of Nepal's strongest health programmes, achieving 89% Penta-3 coverage nationally (NDHS 2022).