title: An outpatient, ambulant-design, controlled human infection model using escalating doses of Salmonella Typhi challenge delivered in sodium bicarbonate solution.
abstract: BACKGROUND
  Typhoid fever is a major global health problem, the control of which is hindered by lack of a suitable animal model in which to study Salmonella Typhi infection. Until 1974, a human challenge model advanced understanding of typhoid and was used in vaccine development. We set out to establish a new human challenge model and ascertain the S. Typhi (Quailes strain) inoculum required for an attack rate of 60%-75% in typhoid-naive volunteers when ingested with sodium bicarbonate solution.
  
  
  METHODS
  Groups of healthy consenting adults ingested escalating dose levels of S. Typhi and were closely monitored in an outpatient setting for 2 weeks. Antibiotic treatment was initiated if typhoid diagnosis occurred (temperature ≥38°C sustained ≥12 hours or bacteremia) or at day 14 in those remaining untreated.
  
  
  RESULTS
  Two dose levels (10(3) or 10(4) colony-forming units) were required to achieve the primary objective, resulting in attack rates of 55% (11/20) or 65% (13/20), respectively. Challenge was well tolerated; 4 of 40 participants fulfilled prespecified criteria for severe infection. Most diagnoses (87.5%) were confirmed by blood culture, and asymptomatic bacteremia and stool shedding of S. Typhi was also observed. Participants who developed typhoid infection demonstrated serological responses to flagellin and lipopolysaccharide antigens by day 14; however, no anti-Vi antibody responses were detected.
  
  
  CONCLUSIONS
  Human challenge with a small inoculum of virulent S. Typhi administered in bicarbonate solution can be performed safely using an ambulant-model design to advance understanding of host-pathogen interactions and immunity. This model should expedite development of diagnostics, vaccines, and therapeutics for typhoid control.
authors: Oxford Vaccine Group, Department of Paediatrics, University of Oxford.
authors: Claire S
authors: CS
authors: Waddington
authors: Thomas C
authors: TC
authors: Darton
authors: Claire
authors: C
authors: Jones
authors: Kathryn
authors: K
authors: Haworth
authors: Anna
authors: A
authors: Peters
authors: Tessa
authors: T
authors: John
authors: Ben A V
authors: BA
authors: Thompson
authors: Simon A
authors: SA
authors: Kerridge
authors: Robert A
authors: RA
authors: Kingsley
authors: Liqing
authors: L
authors: Zhou
authors: Kathryn E
authors: KE
authors: Holt
authors: Ly-Mee
authors: LM
authors: Yu
authors: Stephen
authors: S
authors: Lockhart
authors: Jeremy J
authors: JJ
authors: Farrar
authors: Marcelo B
authors: MB
authors: Sztein
authors: Gordon
authors: G
authors: Dougan
authors: Brian
authors: B
authors: Angus
authors: Myron M
authors: MM
authors: Levine
authors: Andrew J
authors: AJ
authors: Pollard
mesh_terms: D000293:Adolescent; D000328:Adult; D000553:Ambulatory Care; D000907:Antibodies, Bacterial / Q000097:blood; D016470:Bacteremia; D057138:Bacterial Shedding; D005260:Female; D054884:Host-Pathogen Interactions; D006801:Humans; D008297:Male; D008875:Middle Aged; D018448:Models, Immunological; D012485:Salmonella typhi / Q000472:pathogenicity*; D017693:Sodium Bicarbonate; D014435:Typhoid Fever / Q000276:immunology / Q000382:microbiology* / Q000517:prevention & control; D014436:Typhoid-Paratyphoid Vaccines
chemical_list: D000907:Antibodies, Bacterial; D014436:Typhoid-Paratyphoid Vaccines; D017693:Sodium Bicarbonate
keywords: Salmonella Typhi; controlled human infection; enteric infection; human challenge study; typhoid fever