Typhoid Vaccine Acceleration Consortium Malawi: A Phase III, Randomized, Double-blind, Controlled Trial of the Clinical Efficacy of Typhoid Conjugate Vaccine Among Children in Blantyre, Malawi

Abstract

Background Typhoid fever is an acute infection characterized by prolonged fever following the ingestion and subsequent invasion of Salmonella enterica serovar Typhi ( S. Typhi), a human-restricted pathogen. The incidence of typhoid fever has been most reported in children 5–15 years of age, but is increasingly recognized in children younger than 5 years old. There has been a recent expansion of multidrug-resistant typhoid fever globally. Prior typhoid vaccines were not suitable for use in the youngest children in countries with a high burden of disease. This study aims to determine the efficacy of a typhoid conjugate vaccine (TCV) that was recently prequalified by the World Health Organization, by testing it in children 9 months through 12 years of age in Blantyre, Malawi. Methods In this Phase III, individually randomized, controlled, double-blind trial of the clinical efficacy of TCV, 28 000 children 9 months through 12 years of age will be enrolled and randomized in a 1:1 ratio to receive either Vi-TCV or a meningococcal serogroup A conjugate vaccine. A subset of 600 of these children will be further enrolled in an immunogenicity and reactogenicity sub-study to evaluate the safety profile and immune response elicited by Vi-TCV. Recruiting began in February 2018. Results All children will be under passive surveillance for at least 2 years to determine the primary outcome, which is blood culture–confirmed S. Typhi illness. Children enrolled in the immunogenicity and reactogenicity sub-study will have blood drawn before vaccination and at 2 timepoints after vaccination to measure their immune response to vaccination. They will also be followed actively for adverse events and serious adverse events. Conclusions The introduction of a single-dose, efficacious typhoid vaccine into countries with high burden of disease or significant antimicrobial resistance could have a dramatic impact, protecting children from infection and reducing antimicrobial usage and associated health inequity in the world’s poorest places. This trial, the first of a TCV in Africa, seeks to demonstrate the impact and programmatic use of TCVs within an endemic setting. Clinical Trials Registration NCT03299426.

Safety and immunogenicity of co-administration of meningococcal type A and measles–rubella vaccines with typhoid conjugate vaccine in children aged 15–23 months in Burkina Faso

“…11,12 Interim results from a randomized controlled trial in Nepal demonstrated over 81% efficacy in children 9 months to 16 years of age 13 and trials are underway in Malawi and Bangladesh. 14,15 While coadministration of TCV with measles-rubella (MR) vaccine has been studied, 16 TCV has not been tested with routine immunizations in West Africa, where typhoid is endemic and where group A meningococcal conjugate vaccine (MCV-A), which also contains a tetanus toxoid carrier protein, is routinely given at 15 months of age as part of the Expanded Programme on Immunization (EPI). These data are essential for large-scale uptake of TCV in sub-Saharan Africa.…”

Use of Typhoid Vi-Polysaccharide Vaccine as a Vaccine Probe to Delineate Clinical Criteria for Typhoid Fever

“…In the absence of a sensitive typhoid point-of-care diagnostic, a reliable and highly specific clinical rule for predicting typhoid, irrespective of culture positivity, will be useful to guide healthcare workers practicing in endemic, low-resource settings. 50 With a new series of phase III and IV trials being undertaken in Bangladesh, Nepal, and Malawi to evaluate new generation, Vi-protein conjugate vaccines, 16,[51][52][53] our vaccine probe approach should be considered in future analyses to confirm and extend our findings.…”

The Surveillance for Enteric Fever in Asia Project (SEAP), Severe Typhoid Fever Surveillance in Africa (SETA), Surveillance of Enteric Fever in India (SEFI), and Strategic Typhoid Alliance Across Africa and Asia (STRATAA) Population-based Enteric Fever Studies: A Review of Methodological Similarities and Differences

“…A TCV impact assessment is being conducted through Kharadar General Hospital in Karachi, Pakistan (SEAP), in response to an extensively drug-resistant typhoid outbreak [ 19 ]. The University of Maryland and University of Oxford with Typhoid Vaccine Acceleration Consortium (TyVAC) partners are conducting 3 large-scale TCV trials at STRATAA surveillance sites: a cluster-randomized efficacy trial in Bangladesh [ 20 ] and 2 individually randomized efficacy studies in Nepal and Malawi [ 21 , 22 ]. Interim analysis of the Nepal RCT showed that TCV had an 82% vaccine efficacy at 1 year after vaccination in children < 15 years of age [ 23 ].…”