title: Understanding paratyphoid infection: study protocol for the development of a human model of Salmonella enterica serovar Paratyphi A challenge in healthy adult volunteers.
abstract: BACKGROUND
  This study will develop the first human challenge model of paratyphoid infection which may then be taken forward to evaluate paratyphoid vaccine candidates. Salmonella Paratyphi A is believed to cause a quarter of the estimated 20 million cases of enteric fever annually. Epidemiological evidence also suggests that an increasing proportion of the enteric fever burden is attributable to S. Paratyphi infection meriting further attention and interest in vaccine development. Assessment of paratyphoid vaccine efficacy in preclinical studies is complicated by the lack of a small animal model and the human-restricted nature of the infection. The use of experimental human infection in healthy volunteers provides an opportunity to address these problems in a cost-effective manner.
  
  
  METHODS
  Volunteers will ingest virulent S. Paratyphi A bacteria (NVGH308 strain) with a bicarbonate buffer solution to establish the infectious dose resulting in an 'attack rate' of 60-75%. Using an a priori decision-making algorithm, the challenge dose will be escalated or de-escalated to achieve the target attack rate, with the aim of reaching the study end point while exposing as few individuals as possible to infection. The attack rate will be determined by the proportion of paratyphoid infection in groups of 20 healthy adult volunteers, with infection being defined by one or more positive blood cultures (microbiological end point) and/or fever, defined as an oral temperature exceeding 38 °C sustained for at least 12 h (clinical end point); 20-80 participants will be required. Challenge participants will start a 2-week course of an oral antibiotic on diagnosis of infection, or after 14 days follow-up.
  
  
  BACKGROUND
  The strict eligibility criterion aims to minimise risk to participants and their close contacts. Ethical approval has been obtained. The results will be disseminated in a peer-reviewed journal and presented at international congresses.
  
  
  BACKGROUND
  NCT02100397.
authors.affiliation: Oxford Vaccine Group, Department of Paediatrics, University of Oxford, and the NIHR Oxford Biomedical Research Centre, Oxford, Oxfordshire, UK.
authors.forename: David
authors.initials: D
authors.lastname: McCullagh
authors.affiliation: Oxford Vaccine Group, Department of Paediatrics, University of Oxford, and the NIHR Oxford Biomedical Research Centre, Oxford, Oxfordshire, UK.
authors.forename: Hazel C
authors.initials: HC
authors.lastname: Dobinson
authors.affiliation: Oxford Vaccine Group, Department of Paediatrics, University of Oxford, and the NIHR Oxford Biomedical Research Centre, Oxford, Oxfordshire, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: Darton
authors.affiliation: Oxford Vaccine Group, Department of Paediatrics, University of Oxford, and the NIHR Oxford Biomedical Research Centre, Oxford, Oxfordshire, UK.
authors.forename: Danielle
authors.initials: D
authors.lastname: Campbell
authors.affiliation: Oxford Vaccine Group, Department of Paediatrics, University of Oxford, and the NIHR Oxford Biomedical Research Centre, Oxford, Oxfordshire, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Jones
authors.affiliation: Oxford Vaccine Group, Department of Paediatrics, University of Oxford, and the NIHR Oxford Biomedical Research Centre, Oxford, Oxfordshire, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Snape
authors.affiliation: Oxford Vaccine Group, Department of Paediatrics, University of Oxford, and the NIHR Oxford Biomedical Research Centre, Oxford, Oxfordshire, UK.
authors.forename: Zoe
authors.initials: Z
authors.lastname: Stevens
authors.affiliation: Oxford Vaccine Group, Department of Paediatrics, University of Oxford, and the NIHR Oxford Biomedical Research Centre, Oxford, Oxfordshire, UK.
authors.forename: Emma
authors.initials: E
authors.lastname: Plested
authors.affiliation: Oxford Vaccine Group, Department of Paediatrics, University of Oxford, and the NIHR Oxford Biomedical Research Centre, Oxford, Oxfordshire, UK Primary Care Clinical Trials Unit, Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, Oxfordshire, UK.
authors.forename: Merryn
authors.initials: M
authors.lastname: Voysey
authors.affiliation: Oxford Vaccine Group, Department of Paediatrics, University of Oxford, and the NIHR Oxford Biomedical Research Centre, Oxford, Oxfordshire, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Kerridge
authors.affiliation: Novartis Vaccines Institute for Global Health, Siena, Italy.
authors.forename: Laura B
authors.initials: LB
authors.lastname: Martin
authors.affiliation: Nuffield Department of Medicine, University of Oxford, Oxford, Oxfordshire, UK.
authors.forename: Brian
authors.initials: B
authors.lastname: Angus
authors.affiliation: Oxford Vaccine Group, Department of Paediatrics, University of Oxford, and the NIHR Oxford Biomedical Research Centre, Oxford, Oxfordshire, UK Primary Care Clinical Trials Unit, Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, Oxfordshire, UK.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Pollard
mesh_terms: D000293:Adolescent; D000328:Adult; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D002939:Ciprofloxacin / Q000627:therapeutic use; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D010284:Paratyphoid Fever / Q000382:microbiology* / Q000517:prevention & control; D061214:Patient Safety; D010560:Personnel Selection; D012482:Salmonella paratyphi A; D018401:Sample Size; D014435:Typhoid Fever / Q000382:microbiology / Q000517:prevention & control; D014436:Typhoid-Paratyphoid Vaccines; D055815:Young Adult
chemical_list: D000900:Anti-Bacterial Agents; D014436:Typhoid-Paratyphoid Vaccines; D002939:Ciprofloxacin
keywords: BACTERIOLOGY; IMMUNOLOGY; INFECTIOUS DISEASES; MICROBIOLOGY