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Cited by 313Salmonella and Campylobacter epidemiologyBacterial Infections and VaccinesVibrio bacteria research studies

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

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Jin, Celina, Gibani, Malick M, Moore, Maria, Juel, Helene B, Jones, Elizabeth, Meiring, James, Harris, Victoria, Gardner, Jonathan +8 more·2017·The Lancet
DOI 10.1016/s0140-6736(17)32149-9PMC PMC5720597
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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).

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  • Human challenge studies have been used to demonstrate the role of antibodies in protection against malaria and typhoid.

    “human challenge studies offer the opportunity to efficiently assess correlates of protection (Box 2) under controlled circumstances36, and they have been used to demonstrate the role of antibodies in protection against malaria37 and typhoid38.”

    From A guide to vaccinology: from basic principles to new developments (2021) · cites this paper as [38]

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Authors
Jin, C., Gibani, M. M., Moore, M., Juel, H. B., Jones, E., Meiring, J., Harris, V., Gardner, J., Nebykova, A., Kerridge, S. A., Hill, J., Thomaides-Brears, H., Blohmke, C. J., Yu, L.-M., Angus, B., & Pollard, A. J.
Affiliations
University of Oxford (GB)
Corresponding author
Jin, Celina
ORCID
Venue
The Lancet
Publisher
Elsevier BV
Published
2017-12
Volume
390
Issue
10111
Pages
2472-2480
ISSN
  • 0099-5355 (ISSN-L)
  • 0140-6736
DOI
10.1016/s0140-6736(17)32149-9
PMC
PMC5720597
OpenAlex
W2759562520
Cited by
313
References
32
Citations by year
2026: 18 · 2025: 30 · 2024: 25 · 2023: 29 · 2022: 26 · 2021: 43 · 2020: 52 · 2019: 48 · 2018: 39 · 2017: 2
FWCI
43.40
Type
journal article
Language
en
Open access
Licence
Locations
  • The Lancet (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
  • White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
  • Spiral (Imperial College London) (submittedVersion, cc-by)
Funders
  • Bill and Melinda Gates Foundation (OPP1084259)
  • Pfizer
  • AstraZeneca
  • GlaxoSmithKline
  • Gilead Sciences
  • Wellcome Trust
  • European Commission
Topics
  • Life Sciences › Agricultural and Biological Sciences › Food Science › Salmonella and Campylobacter epidemiology
  • Life Sciences › Immunology and Microbiology › Microbiology › Bacterial Infections and Vaccines
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Vibrio bacteria research studies
Keywords
typhoid fever, Salmonella typhi, Vi polysaccharide vaccine, controlled human infection model, oral challenge, vaccine efficacy, immunogenicity, bacteremia, vaccine safety, injection site reactions, meningococcal vaccine
MeSH terms
Adult, Female, Humans, Male, Salmonella typhi, Tetanus Toxoid, Typhoid Fever, Typhoid-Paratyphoid Vaccines, Vaccines, Conjugate

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