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

SummaryBackgroundSalmonella 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.MethodsIn 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.FindingsBetween 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).InterpretationVi-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...

Diagnostic host gene signature for distinguishing enteric fever from other febrile diseases

“…Finally, to validate the induction of the diagnostic gene signature in blood culture‐confirmed enteric fever cases, we performed high‐throughput qPCR in samples collected during an independent typhoid CHIM (—qPCR; Jin et al , ) and in the Nepali cohort. Transcription of the 5‐gene signature was increased at the time of diagnosis in most participants with culture‐confirmed enteric fever in both sample sets (Fig D and E).…”

“…T2: Oxford typhoid CHIM study 2; P1: Oxford paratyphoid CHIM. high-throughput qPCR in samples collected during an independent typhoid CHIM (Appendix Table S2 -qPCR;Jin et al, 2017) and in the Nepali cohort. Transcription of the 5-gene signature was increased at the time of diagnosis in most participants with cultureconfirmed enteric fever in both sample sets ( Fig 5D and E).…”

“…Samples used in the validation cohort were collected from a second typhoid challenge model performed as part of a vaccine efficacy study (Study: T2), in which healthy adult volunteers ingested a single dose of S. Typhi Quailes strain (1-5 × 10 4 , n = 99) 4 weeks after oral vaccination with Ty21a, M01ZH09 or placebo (Darton et al, 2016). Lastly, samples collected from the control arm of a further vaccine efficacy challenge study, in which participants received meningococcal ACWY-CRM conjugate vaccine (MENVEO â , GlaxoSmithKline) prior to challenge, were used for the independent qPCR validation experiment (Jin et al, 2017). The clinical and molecular results of these studies have been described previously (Waddington et al, 2014;Darton et al, 2016;Dobinson et al, 2017;Jin et al, 2017).…”

Typhoid conjugate vaccines: making vaccine history in Africa

“…Recent data from the Oxford typhoid CHIM, where healthy volunteers received Tybar-TCV, Vi-PS, or control vaccine and then 1 month later received oral challenge with live typhoid bacteria, demonstrated a protective efficacy of 87.1% when a clinical end point of fever >38°C for >12 h followed by positive blood culture was used [7]. Both the immunogenicity and CHIM efficacy data were important in securing WHO pre-qualification.…”

“…However, the recent WHO pre-qualification of the TCV Typbar-TCV ® [6] following promising vaccine efficacy results from the Oxford typhoid controlled human infection model (CHIM) [7] provides hope that there is now a vaccine which may have impact on global typhoid burden.…”