Efficacy and immunogenicity of a Vi-tetanus toxoid conjugate vaccine in the prevention of typhoid fever using a controlled human infection model of Salmonella Typhi: a randomised controlled, phase 2b trial

Abstract

Background: Salmonella enterica serovar Typhi (S Typhi) is responsible for an estimated 20 million infections and 200 000 deaths each year in resource poor regions of the world. Capsular Vi-polysaccharide-protein conjugate vaccines (Vi-conjugate vaccines) are immunogenic and can be used from infancy but there are no efficacy data for the leading candidate vaccine being considered for widespread use. To address this knowledge gap, we assessed the efficacy of a Vi-tetanus toxoid conjugate vaccine using an established human infection model of S Typhi.

Methods: In this single-centre, randomised controlled, phase 2b study, using an established outpatient-based human typhoid infection model, we recruited healthy adult volunteers aged between 18 and 60 years, with no previous history of typhoid vaccination, infection, or prolonged residency in a typhoid-endemic region. Participants were randomly assigned (1:1:1) to receive a single dose of Vi-conjugate (Vi-TT), Vi-polysaccharide (Vi-PS), or control meningococcal vaccine with a computer-generated randomisation schedule (block size 6). Investigators and participants were masked to treatment allocation, and an unmasked team of nurses administered the vaccines. Following oral ingestion of S Typhi, participants were assessed with daily blood culture over a 2-week period and diagnosed with typhoid infection when meeting pre-defined criteria. The primary endpoint was the proportion of participants diagnosed with typhoid infection (ie, attack rate), defined as persistent fever of 38°C or higher for 12 h or longer or S Typhi bacteraemia, following oral challenge administered 1 month after Vi-vaccination (Vi-TT or Vi-PS) compared with control vaccination. Analysis was per protocol. This trial is registered with ClinicalTrials.gov, number NCT02324751, and is ongoing.

Findings: Between Aug 18, 2015, and Nov 4, 2016, 112 participants were enrolled and randomly assigned; 34 to the control group, 37 to the Vi-PS group, and 41 to the Vi-TT group. 103 participants completed challenge (31 in the control group, 35 in the Vi-PS group, and 37 in the Vi-TT group) and were included in the per-protocol population. The composite criteria for typhoid diagnosis was met in 24 (77%) of 31 participants in the control group, 13 (35%) of 37 participants in the Vi-TT group, and 13 (35%) of 35 participants in the Vi-PS group to give vaccine efficacies of 54·6% (95% CI 26·8-71·8) for Vi-TT and 52·0% (23·2-70·0) for Vi-PS. Seroconversion was 100% in Vi-TT and 88·6% in Vi-PS participants, with significantly higher geometric mean titres detected 1-month post-vaccination in Vi-TT vaccinees. Four serious adverse events were reported during the conduct of the study, none of which were related to vaccination (one in the Vi-TT group and three in the Vi-PS group).

Interpretation: Vi-TT is a highly immunogenic vaccine that significantly reduces typhoid fever cases when assessed using a stringent controlled model of typhoid infection. Vi-TT use has the potential to reduce both the burden of typhoid fever and associated health inequality.

Funding: The Bill & Melinda Gates Foundation and the European Commission FP7 grant, Advanced Immunization Technologies (ADITEC).

Figure 1

Trial profile Vi-TT=Vi-tetanus toxoid conjugate vaccine. Vi-PS=Vi-polysaccharide vaccine.

Figure 2

Proportion of participants diagnosed with typhoid infection (A) Cumulative proportion of participants with typhoid infection (meeting predefined microbiological, clinical criteria, or both) after Salmonella Typhi (S Typhi) challenge. (B) Cumulative proportion of participants with fever 38·0°C or higher preceding S Typhi bacteraemia (time to event measured from time of challenge agent ingestion to time of first positive blood culture sampling or time of first recorded fever ≥38·0°C). Vi-TT=Vi-tetanus toxoid conjugate vaccine. Vi-PS=Vi-polysaccharide vaccine.

Figure 3

Anti-Vi IgG titres measured following vaccination (A) Anti-Vi IgG titres measured at the time of challenge, comparison between typhoid diagnosed (open symbols) and undiagnosed (closed symbols). (B) Anti-Vi IgG titres measured at baseline (pre-vaccination) and at the time of challenge (median 28 days post-vaccination). (C) Anti-Vi IgG2 titres measured at the time of challenge in Vi-TT and Vi-PS diagnosed (open symbols) and undiagnosed (closed symbols). Vi-TT=Vi-tetanus toxoid conjugate vaccine. Vi-PS=Vi-polysaccharide vaccine.