Efficacy of typhoid conjugate vaccine: final analysis of a 4-year, phase 3, randomised controlled trial in Malawian children

Abstract

Background: Randomised controlled trials of typhoid conjugate vaccines among children in Africa and Asia have shown high short-term efficacy. Data on the durability of protection beyond 2 years are sparse. We present the final analysis of a randomised controlled trial in Malawi, encompassing more than 4 years of follow-up, with the aim of investigating vaccine efficacy over time and by age group.

Methods: In this phase 3, double-blind, randomised controlled efficacy trial in Blantyre, Malawi, healthy children aged 9 months to 12 years were randomly assigned (1:1) by an unmasked statistician to receive a single dose of Vi polysaccharide conjugated to tetanus toxoid vaccine (Vi-TT) or meningococcal capsular group A conjugate (MenA) vaccine. Children had to have no previous history of typhoid vaccination and reside in the study areas for inclusion and were recruited from government schools and health centres. Participants, their parents or guardians, and the study team were masked to vaccine allocation. Nurses administering vaccines were unmasked. We did surveillance for febrile illness from vaccination until follow-up completion. The primary outcome was first occurrence of blood culture-confirmed typhoid fever. Eligible children who were randomly assigned and vaccinated were included in the intention-to-treat analyses. This trial is registered at ClinicalTrials.gov, NCT03299426.

Findings: Between Feb 21, 2018, and Sept 27, 2018, 28 130 children were vaccinated; 14 069 were assigned to receive Vi-TT and 14 061 to receive MenA. After a median follow-up of 4·3 years (IQR 4·2-4·5), 24 (39·7 cases per 100 000 person-years) children in the Vi-TT group and 110 (182·7 cases per 100 000 person-years) children in the MenA group 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% CI 66·3-86·1), and 163 (129-222) children needed to be vaccinated to prevent one case. Efficacies by age group were 70·6% (6·4-93·0) for children aged 9 months to 2 years; 79·6% (45·8-93·9) for children aged 2-4 years; and 79·3% (63·5-89·0) for children aged 5-12 years.

Interpretation: A single dose of Vi-TT is durably efficacious for at least 4 years among children aged 9 months to 12 years and shows efficacy in all age groups, including children younger than 2 years. These results support current WHO recommendations in typhoid-endemic areas for mass campaigns among children aged 9 months to 15 years, followed by routine introduction in the first 2 years of life.

Funding: Bill & Melinda Gates Foundation.

Figure 1

Trial profile 248 participants were excluded from the per-protocol analysis due to a participant identification number assignment error or vaccine administration error. MenA=meningococcal capsular group A conjugate vaccine. Vi-TT=Vi polysaccharide tetanus toxoid typhoid conjugate vaccine. *166 pairs of children received the same participant identification number due to a duplicate bar code printing error. The second participant who received the duplicate number within a pair was assigned a new number and excluded from the per-protocol analysis.

Figure 2

Number of blood-culture positive typhoid cases in the intention-to-treat population, by date and vaccine group Dates of COVID-19 surveillance interruptions are shown with dotted vertical lines. MenA=meningococcal capsular group A conjugate vaccine. Vi-TT=Vi polysaccharide tetanus toxoid typhoid conjugate vaccine.

Figure 3

Kaplan-Meier estimates of the cumulative incidence of blood-culture positive typhoid fever Curves begin on vaccination day 0 and are for the intention-to-treat population by vaccine group. MenA=meningococcal capsular group A conjugate vaccine. Vi-TT=Vi polysaccharide tetanus toxoid typhoid conjugate vaccine.