An Outpatient, Ambulant-Design, Controlled Human Infection Model Using Escalating Doses of Salmonella Typhi Challenge Delivered in Sodium Bicarbonate Solution

• Published in: Clinical infectious diseases Vol. 58; no. 9; pp. 1230 - 1240
• Main Authors: Waddington, Claire S., Darton, Thomas C., Jones, Claire, Haworth, Kathryn, Peters, Anna, John, Tessa, Thompson, Ben A. V., Kerridge, Simon A., Kingsley, Robert A., Zhou, Liqing, Holt, Kathryn E., Yu, Ly-Mee, Lockhart, Stephen, Farrar, Jeremy J., Sztein, Marcelo B., Dougan, Gordon, Angus, Brian, Levine, Myron M., Pollard, Andrew J.
• Format: Journal Article
• Language: English
• Published: Oxford OXFORD UNIVERSITY PRESS 01.05.2014; Oxford University Press
• Subjects: Adolescent; Adult; Ambulatory Care; and Commentaries; Antibodies, Bacterial - blood; Antigens; ARTICLES AND COMMENTARIES; Bacteremia; Bacterial Shedding; Biological and medical sciences; Blood culture; Colony forming units assay; Dosage; Drug dosages; Female; Host-Pathogen Interactions; Human subjects; Humans; Immunology; Infections; Infectious diseases; Male; Medical sciences; Middle Aged; Models, Immunological; Pharmacology; Salmonella; Salmonella typhi; Salmonella typhi - pathogenicity; Sodium Bicarbonate; Symptoms; Temperature measurement; Typhoid; Typhoid fever; Typhoid Fever - immunology; Typhoid Fever - microbiology; Typhoid Fever - prevention & control; Typhoid-Paratyphoid Vaccines; Human; Infection; Increasing dose; Sodium; Salmonella typhi; Bacteria; Models; Ambulatory; Enterobacteriaceae; typhoid fever; enteric infection; human challenge study; controlled human infection; Salmonella Typhi
• ISSN: 1058-4838; 1537-6591; 1537-6591
• DOI: 10.1093/cid/ciu078

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 typhoidnaive 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.