Protection by vaccination of children against typhoid fever with a Vi-tetanus toxoid conjugate vaccine in urban Bangladesh: a cluster-randomised trial

Abstract

Summary Background Typhoid fever remains a major cause of morbidity and mortality in low-income and middle-income countries. Vi-tetanus toxoid conjugate vaccine (Vi-TT) is recommended by WHO for implementation in high-burden countries, but there is little evidence about its ability to protect against clinical typhoid in such settings. Methods We did a participant-masked and observer-masked cluster-randomised trial preceded by a safety pilot phase in an urban endemic setting in Dhaka, Bangladesh. 150 clusters, each with approximately 1350 residents, were randomly assigned (1:1) to either Vi-TT or SA 14-14-2 Japanese encephalitis (JE) vaccine. Children aged 9 months to less than 16 years were invited via parent or guardian to receive a single, parenteral dose of vaccine according to their cluster of residence. The study population was followed for an average of 17·1 months. Total and overall protection by Vi-TT against blood culture-confirmed typhoid were the primary endpoints assessed in the intention-to-treat population of vaccinees or all residents in the clusters. A subset of approximately 4800 participants was assessed with active surveillance for adverse events. The trial is registered at www.isrctn.com , ISRCTN11643110. Findings 41 344 children were vaccinated in April–May, 2018, with another 20 412 children vaccinated at catch-up vaccination campaigns between September and December, 2018, and April and May, 2019. The incidence of typhoid fever (cases per 100 000 person-years) was 635 in JE vaccinees and 96 in Vi-TT vaccinees (total Vi-TT protection 85%; 97·5% CI 76 to 91, p<0·0001). Total vaccine protection was consistent in different age groups, including children vaccinated at ages under 2 years (81%; 95% CI 39 to 94, p=0·0052). The incidence was 213 among all residents in the JE clusters and 93 in the Vi-TT clusters (overall Vi-TT protection 57%; 97·5% CI 43 to 68, p<0·0001). We did not observe significant indirect vaccine protection by Vi-TT (19%; 95% CI −12 to 41, p=0·20). The vaccines were well tolerated, and no serious adverse events judged to be vaccine-related were observed. Interpretation Vi-TT provided protection against typhoid fever to children vaccinated between 9 months and less than 16 years. Longer-term follow-up will be needed to assess the duration of protection and the need for booster doses. Funding The study was funded by the Bill & Melinda Gates Foundation.

Typhoid Conjugate Vaccine: An Urgent Tool to Combat Typhoid and Tackle Antimicrobial Resistance

“…A randomized clinical trial of Typbar TCV, in children between 9 months and 15 years of age in Nepal, showed an efficacy of 82% [ 20 ]. Similar results were observed in a cluster-randomized trial of Typbar TCV in Bangladesh, which showed an efficacy of 85% among infants and children aged 9 months to 16 years [ 21 ]. The study also found no serious vaccine-related adverse events.…”

Effectiveness of Typhoid Conjugate Vaccine in Zimbabwe used in response to an outbreak among children and young adults: a matched case control study

“…In a similar age population, a recent cluster randomized clinical trial in Bangladesh showed similar protection provided by Vi-TT (85%; 95% CI 76-91). 25 During an emergent extensively drug-resistant (XDR) S. typhi outbreak in Hyderabad Pakistan, a population-based prospective cohort study estimated VE TF at 95% (95% CI 93-96). 26 However, in a similar design to our study in a peri-urban community of Karachi, in a matched case-control study following a Vi-TT mass immunisation campaign, the estimated VE was 72% (95% CI 34-88) among children six months to 15 years, which was closer to our results among children in Harare.…”

Typhoid Conjugate Vaccines: Advancing the Research and Public Health Agendas

“…Similar vaccine efficacy was observed in Malawi, with an efficacy estimate of 80.7% (intention-to-treat population) and 83.7% (per protocol population) against blood culture-confirmed typhoid fever among children 9 months through 12 years of age, after 18 months of study follow-up ( Table 1 ) [ 21 ]. In a cluster-randomized trial in Dhaka, Bangladesh total effectiveness of TCV was 85% among vaccinated children aged 9 months to 15 years [ 22 ]. Importantly, total effectiveness remained high across age groups, including among children younger than 2 years of age, in whom total effectiveness was 81% [ 22 ].…”

“…In a cluster-randomized trial in Dhaka, Bangladesh total effectiveness of TCV was 85% among vaccinated children aged 9 months to 15 years [ 22 ]. Importantly, total effectiveness remained high across age groups, including among children younger than 2 years of age, in whom total effectiveness was 81% [ 22 ]. High efficacy after a single dose, and the consistency of results in different settings and age groups, supports broad use of TCV ( Table 1 ).…”