Waddington, C.S., Darton, T.C., Jones, C. et al. (16 more authors) (2014) An outpatient, ambulant-design, controlled human infection model using escalating doses of Salmonella Typhi challenge delivered in sodium bicarbonate solution. Clinical Infectious Diseases, 58 (9). 1230 - 1240. ISSN 1058-4838
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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited |
Keywords: | Salmonella Typhi; controlled human infection; enteric infection; human challenge study; typhoid fever; Adolescent; Adult; Ambulatory Care; Antibodies, Bacterial; Bacteremia; Bacterial Shedding; Female; Host-Pathogen Interactions; Humans; Male; Middle Aged; Models, Immunological; Salmonella typhi; Sodium Bicarbonate; Typhoid Fever; Typhoid-Paratyphoid Vaccines |
Dates: |
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Institution: | The University of Sheffield |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 10 Jun 2015 11:37 |
Last Modified: | 10 Jun 2015 11:37 |
Published Version: | http://dx.doi.org/10.1093/cid/ciu078 |
Status: | Published |
Publisher: | Oxford University Press |
Refereed: | Yes |
Identification Number: | 10.1093/cid/ciu078 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:86784 |