An observer-blinded, cluster randomised trial of a typhoid conjugate vaccine in an urban South Indian cohort.

Background: Typhoid fever causes nearly 110,000 deaths among 9.24 million cases globally and disproportionately affects developing countries. As a control measure in such regions, typhoid conjugate vaccines (TCVs) are recommended by the World Health Organization (WHO). We present here the protocol of a cluster randomised vaccine trial to assess the impact of introducing TyphiBEV® vaccine to those between 1 and 30 years of age in a high-burden setting.

Methods: The primary objective is to determine the relative and absolute rate reduction of symptomatic, blood-culture-confirmed S. Typhi infection among participants vaccinated with TyphiBEV® in vaccine clusters compared with the unvaccinated participants in non-vaccine clusters. The study population is residents of 30 wards of Vellore (a South Indian city) with participants between the ages of 1 and 30 years who provide informed consent. The wards will be divided into 60 contiguous clusters and 30 will be randomly selected for its participants to receive TyphiBEV® at the start of the study. No placebo/control is planned for the non-intervention clusters, which will receive the vaccine at the end of the trial. Participants will not be blinded to their intervention. Episodes of typhoid fever among participants will be captured via stimulated, passive fever surveillance in the area for 2 years after vaccination, which will include the most utilised healthcare facilities. Observers blinded to the participants' intervention statuses will record illness details. Relative and absolute rate reductions will be calculated at the end of this surveillance and used to estimate vaccine effectiveness.

Discussion: The results from our trial will allow countries to make better-informed decisions regarding the TCV that they will roll-out and may improve the global supplies and affordability of the vaccines.

Trial Registration: Clinical Trials Registry of India (CTRI) CTRI/2022/03/041314. Prospectively registered on 23 March 2022 ( https://ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=62548&EncHid=&userName=vellore%20typhoid ). CTRI collects the full WHO Trial Registration Data Set.