title: Using a Human Challenge Model of Infection to Measure Vaccine Efficacy: A Randomised, Controlled Trial Comparing the Typhoid Vaccines M01ZH09 with Placebo and Ty21a.
abstract: Typhoid persists as a major cause of global morbidity. While several licensed vaccines to prevent typhoid are available, they are of only moderate efficacy and unsuitable for use in children less than two years of age. Development of new efficacious vaccines is complicated by the human host-restriction of Salmonella enterica serovar Typhi (S. Typhi) and lack of clear correlates of protection. In this study, we aimed to evaluate the protective efficacy of a single dose of the oral vaccine candidate, M01ZH09, in susceptible volunteers by direct typhoid challenge.
  
  
  
  We performed a randomised, double-blind, placebo-controlled trial in healthy adult participants at a single centre in Oxford (UK). Participants were allocated to receive one dose of double-blinded M01ZH09 or placebo or 3-doses of open-label Ty21a. Twenty-eight days after vaccination, participants were challenged with 104CFU S. Typhi Quailes strain. The efficacy of M01ZH09 compared with placebo (primary outcome) was assessed as the percentage of participants reaching pre-defined endpoints constituting typhoid diagnosis (fever and/or bacteraemia) during the 14 days after challenge. Ninety-nine participants were randomised to receive M01ZH09 (n = 33), placebo (n = 33) or 3-doses of Ty21a (n = 33). After challenge, typhoid was diagnosed in 18/31 (58.1% [95% CI 39.1 to 75.5]) M01ZH09, 20/30 (66.7% [47.2 to 87.2]) placebo, and 13/30 (43.3% [25.5 to 62.6]) Ty21a vaccine recipients. Vaccine efficacy (VE) for one dose of M01ZH09 was 13% [95% CI -29 to 41] and 35% [-5 to 60] for 3-doses of Ty21a. Retrospective multivariable analyses demonstrated that pre-existing anti-Vi antibody significantly reduced susceptibility to infection after challenge; a 1 log increase in anti-Vi IgG resulting in a 71% decrease in the hazard ratio of typhoid diagnosis ([95% CI 30 to 88%], p = 0.006) during the 14 day challenge period. Limitations to the study included the requirement to limit the challenge period prior to treatment to 2 weeks, the intensity of the study procedures and the high challenge dose used resulting in a stringent model.
  
  
  
  Despite successfully demonstrating the use of a human challenge study to directly evaluate vaccine efficacy, a single-dose M01ZH09 failed to demonstrate significant protection after challenge with virulent Salmonella Typhi in this model. Anti-Vi antibody detected prior to vaccination played a major role in outcome after challenge.
  
  
  
  ClinicalTrials.gov (NCT01405521) and EudraCT (number 2011-000381-35).
authors.affiliation: Oxford Vaccine Group, Department of Paediatrics, and the NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, United Kingdom.
authors.forename: Thomas C
authors.identifier: 0000-0003-2209-9956
authors.initials: TC
authors.lastname: Darton
authors.affiliation: Oxford Vaccine Group, Department of Paediatrics, and the NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, United Kingdom.
authors.forename: Claire
authors.initials: C
authors.lastname: Jones
authors.affiliation: Oxford Vaccine Group, Department of Paediatrics, and the NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, United Kingdom.
authors.forename: Christoph J
authors.initials: CJ
authors.lastname: Blohmke
authors.affiliation: Oxford Vaccine Group, Department of Paediatrics, and the NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, United Kingdom.
authors.forename: Claire S
authors.initials: CS
authors.lastname: Waddington
authors.affiliation: Oxford Vaccine Group, Department of Paediatrics, and the NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, United Kingdom.
authors.forename: Liqing
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Oxford Vaccine Group, Department of Paediatrics, and the NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, United Kingdom.
authors.forename: Anna
authors.initials: A
authors.lastname: Peters
authors.affiliation: Oxford Vaccine Group, Department of Paediatrics, and the NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, United Kingdom.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Haworth
authors.affiliation: Oxford Vaccine Group, Department of Paediatrics, and the NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, United Kingdom.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Sie
authors.affiliation: Oxford Vaccine Group, Department of Paediatrics, and the NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, United Kingdom.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Green
authors.affiliation: Oxford Vaccine Group, Department of Paediatrics, and the NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, United Kingdom.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Jeppesen
authors.affiliation: Oxford Vaccine Group, Department of Paediatrics, and the NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, United Kingdom.
authors.forename: Maria
authors.initials: M
authors.lastname: Moore
authors.affiliation: Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, United Kingdom.
authors.forename: Ben A V
authors.initials: BA
authors.lastname: Thompson
authors.affiliation: Oxford Vaccine Group, Department of Paediatrics, and the NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, United Kingdom.
authors.forename: Tessa
authors.initials: T
authors.lastname: John
authors.affiliation: Microbial Pathogenesis Group, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Kingsley
authors.affiliation: Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, United Kingdom.
authors.forename: Ly-Mee
authors.initials: LM
authors.lastname: Yu
authors.affiliation: Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, United Kingdom.
authors.forename: Merryn
authors.initials: M
authors.lastname: Voysey
authors.affiliation: Emergent Product Development UK Ltd, Emergent BioSolutions, Wokingham, United Kingdom.
authors.forename: Zoe
authors.initials: Z
authors.lastname: Hindle
authors.affiliation: Emergent Product Development UK Ltd, Emergent BioSolutions, Wokingham, United Kingdom.
authors.forename: Stephen
authors.initials: S
authors.lastname: Lockhart
authors.affiliation: Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Marcelo B
authors.initials: MB
authors.lastname: Sztein
authors.affiliation: Microbial Pathogenesis Group, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
authors.forename: Gordon
authors.initials: G
authors.lastname: Dougan
authors.affiliation: Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Brian
authors.initials: B
authors.lastname: Angus
authors.affiliation: Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Myron M
authors.initials: MM
authors.lastname: Levine
authors.affiliation: Oxford Vaccine Group, Department of Paediatrics, and the NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, United Kingdom.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Pollard
mesh_terms: D000328:Adult; D000907:Antibodies, Bacterial / Q000097:blood; D004311:Double-Blind Method; D005260:Female; D064368:Healthy Volunteers; D006805:Human Experimentation; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D008297:Male; D010919:Placebos; D011135:Polysaccharides, Bacterial / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology; D012485:Salmonella typhi / Q000276:immunology; D014435:Typhoid Fever / Q000175:diagnosis / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control*; D014436:Typhoid-Paratyphoid Vaccines / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology; D014613:Vaccines, Attenuated / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology; D055815:Young Adult
chemical_list: D000907:Antibodies, Bacterial; D007074:Immunoglobulin G; D010919:Placebos; D011135:Polysaccharides, Bacterial; C072772:Ty21a typhoid vaccine; D014436:Typhoid-Paratyphoid Vaccines; D014613:Vaccines, Attenuated; C503988:typhoid vaccine M01ZH09