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 health inequality.FundingThe Bill & Melinda Gates Foundation and the European Commission FP7 grant, Advanced Immunization Technologies (ADITEC).
Highlights
Salmonella enterica subspecies enterica serovar Typhi (S Typhi) is the leading cause of enteric fever affecting 12·5–20·6 million people in regions of the world with inadequate water quality and poor sanitation,[1,2] in south Asia and sub-Saharan Africa
The first capsular Vi-polysaccharide-protein conjugate (Vi-conjugate) vaccine efficacy trial, published in 2001, estimated efficacy at 89% following two doses of a prototype Vi-rEPA vaccine (Vi conjugated to recombinant Pseudomonas aeruginosa exotoxin A) in children aged between 2–5 years
We have shown that this Vi-tetanus toxoid conjugate (Vi-TT) vaccine is safe, highly immunogenic, and prevents 55% of typhoid infections and up to 87% of infections, when using alternative definitions of typhoid fever
Summary
Salmonella enterica subspecies enterica serovar Typhi (S Typhi) is the leading cause of enteric fever affecting 12·5–20·6 million people in regions of the world with inadequate water quality and poor sanitation,[1,2] in south Asia and sub-Saharan Africa. Children are especially susceptible to infection and have a high burden of illness.[3] Mortality is estimated at 1% and about 3% of individuals become chronic carriers.[4,5] The large burden of febrile illness associated with typhoid fever in some affected populations—eg, 15% of children with fever attending a health-care facility in Nepal during one rainy season,[6] drives widespread over-the-counter, and pre scription antibiotic use.[7] Antimicrobial resistance (AMR) is increasingly recognised among S Typhi lineages spreading from south Asia to Africa, with resistance to first-line www.thelancet.com Vol 390 December 2, 2017. The cost and logistical difficulties associated with undertaking large field efficacy trials has contributed to the paucity of published data and has hindered the advancement of Vi-conjugate vaccines
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
