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Efficacy of Typhoid Conjugate Vaccine: Final Analysis of a Four-Year, Randomised Controlled Trial in Malawian Children
19 Pages Posted: 7 Apr 2023More...
Background: Randomised controlled trials of typhoid conjugate vaccines among children in Africa and Asia demonstrate high short-term efficacy. Data on durability of protection beyond two years, particularly in younger children, are limited. We present the final analysis of a randomised controlled trial in Malawi, encompassing more than 4 years of follow-up.
Methods: In a phase 3 double-blinded efficacy trial, healthy children aged 9 months-12 years were randomly assigned in a 1:1 ratio to receive a single dose of Vi polysaccharide conjugated to tetanus toxoid vaccine (Vi-TT) or meningococcal capsular group A conjugate (MenA) vaccine. We conducted passive surveillance for febrile illness from vaccination (February-September 2018) through September 2022. The primary outcome was first episode of blood culture-confirmed typhoid fever.
Results: Between 21 February-27 September 2018, 28,130 children were vaccinated; 14,069 were assigned to receive Vi-TT and 14,061 assigned to receive MenA. After a median follow-up of 4·3 years (interquartile range: 4·2-4·5), 24 children in the Vi-TT group (39·7 cases/100,000 person-years) and 110 children in the MenA group (182·7 cases/100,000 person-years) were diagnosed with a first episode of blood culture-confirmed typhoid fever. In the intention-to-treat population, efficacy of Vi-TT was 78·3% (95% confidence interval (CI): 66·3%- 86·1%), and the number of children needed to vaccinate to prevent one case was 163. Over 4 years, vaccine efficacy was estimated to fall by 1.3% per year (p=0·77). Efficacies by age-group were 70·6% (95% CI: 6·4%- 93·0%) in children aged 9 months to <2 years, 79.6% (95% CI: 45·8%-93·9%) in children 2 to <5 years, and 79·3% (95% CI: 63·5%-89·0%) in children 5-12 years.
Conclusions: A single dose of Vi-TT is durably efficacious in preventing blood culture-confirmed typhoid fever for >4 years among children aged 9 months-12 years.
Trial Registration: ClinicalTrials.gov number NCT03299426.
Funding: This study was funded by a grant from the Bill & Melinda Gates Foundation (OPP1151153).
Declaration of Interest: PDP, YL, JEM, NC, PP, TM, FM, RW, HCB, FS, GK, QD, NNN, OMN, TG, DS, LPJ, JMT, MBL, RSH, and MAG have no competing interests to declare. YL, DS, LPJ, MBL, and KMN receive funding from the TyVAC grant (OPP1151153). KMN is on the World Health Organization Strategic Advisory Group of Experts on Immunization (SAGE).
Ethical Approval: Local ethics approval was obtained from the Malawi National Health and Science Review Committee, and international ethics approval from the University of Liverpool Ethical Review Board, and the University of Maryland Baltimore Institutional Review Board. Results and safety were regularly reviewed by a Data and Safety Monitoring Board.
Keywords: Malawi, typhoid conjugate vaccine, Africa, efficacy, pediatrics
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