Safety and Efficacy of a Typhoid Conjugate Vaccine in Malawian Children

Abstract

Background Typhoid fever caused by multidrug-resistant H58 Salmonella Typhi is an increasing public-health threat in sub-Saharan Africa. We present phase 3 efficacy data from an African trial of a Vi-polysaccharide typhoid conjugate vaccine (Vi-TCV). Methods Children aged 9 months to 12 years in Blantyre, Malawi were randomized (1:1) in a double-blind trial to receive Vi-TCV (single dose) or group-A meningococcal control vaccine (MenA).The primary outcome was blood culture-confirmed typhoid fever. We present the primary vaccine efficacy (VE) and safety outcomes after 18–24 months of follow-up. Results This intention-to-treat (ITT) analysis included 28,130 children, comprising 14,069 children who received Vi-TCV and 14,061 children who received MenA. Blood culture-confirmed typhoid fever occurred in 12 children in the Vi-TCV group (46.9 per 100,000 person-years) and 62 children in the MenA group (243 per 100,000 person-years). Overall VE was 80.7% (95% confidence interval (CI): 64.2% to 89.6%) in an ITT analysis, and 83.7% (95% CI: 68.1%−91.6%) in a per-protocol analysis. In total, 130 serious adverse events occurred in the first 6 months after vaccination (52 in Vi-TCV group and 78 in MenA group), including 6 deaths (all in MenA group). No serious adverse event was considered by the investigator as related to study vaccination. Conclusions Vi-TCV reduced blood culture-confirmed typhoid fever among Malawian children aged 9 months to 12 years. (Funded by the Bill & Melinda Gates Foundation; ClinicalTrials.gov number NCT03299426 .)

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

“…In Africa, recent results of a phase three, double blind Vi-TT efficacy trial conducted in Malawi among children nine months to 12 years showed 80.7% protection (95% CI 64.2-89.6) in intention to treat and 83.7% (95% CI 68.1-91.6) in per protocol analysis. 27 This study is important as it confirms the efficacy of mass vaccination for TF when used under real field and programmatic conditions in the African context as part of an outbreak response.…”

“…In Africa, recent results of a phase three, double blind Vi-TT efficacy trial conducted in Malawi among children nine months to 12 years showed 80.7% protection (95% CI 64.2–89.6) in intention to treat and 83.7% (95% CI 68.1–91.6) in per protocol analysis. 27…”

Typhoid Conjugate Vaccines: Advancing the Research and Public Health Agendas

“…When the analysis was restricted to the WHO clinical diagnosis of typhoid fever, those presenting with at least 3 days of fever, the efficacy estimate increased to 85.1% [ 20 ]. 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 ].…”

Controlled Human Infection Models To Accelerate Vaccine Development

“…Similarly, a clusterrandomized study of over 60,000 children in Bangladesh found an overall vaccine protection of 57 percent (443). A Phase 3 study of over 28,000 children in Malawi compared TCV against meningococcus A vaccine and found an overall efficacy of 81 percent (444). Two Phase 2 studies in Burkina Faso confirmed the safety of TCV and its compatibility with other routine immunizations (445,446).…”