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Observational Study
. 2014 May;58(9):1230-40.
doi: 10.1093/cid/ciu078. Epub 2014 Feb 10.

An outpatient, ambulant-design, controlled human infection model using escalating doses of Salmonella Typhi challenge delivered in sodium bicarbonate solution

Affiliations
Observational Study

An outpatient, ambulant-design, controlled human infection model using escalating doses of Salmonella Typhi challenge delivered in sodium bicarbonate solution

Claire S Waddington et al. Clin Infect Dis. 2014 May.

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.

Keywords: Salmonella Typhi; controlled human infection; enteric infection; human challenge study; typhoid fever.

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Figures

Figure 1.
Figure 1.
Dose-escalation decision algorithm. Abbreviation: pts, patients.
Figure 2.
Figure 2.
Participant recruitment, enrollment, and disposition flow diagram for clinical study OVG 2009/10. Abbreviations: CFU, colony-forming units; S. Typhi, Salmonella enterica serovar Typhi.
Figure 3.
Figure 3.
Kaplan-Meier plots demonstrating time to diagnostic endpoints including all diagnoses (A), those diagnosed using clinical (B) and microbiological (C) criteria, and time to fever (first temperature ≥38°C; [D]) and to first positive blood culture (E), following challenge at 2 dose levels (103 or 104 colony-forming units [CFU]) of Salmonella Typhi (Quailes strain). Shaded gray area, end of 2-week observation period (all remaining participants started on antibiotic therapy); dotted gray line with circle symbols, participants challenged with 103 CFU; dashed black lines with square symbols, participants challenged with 104 CFU.

Comment in

  • Reply to Farmakiotis et al.
    Waddington CS, Darton TC, Angus B, Pollard AJ. Waddington CS, et al. Clin Infect Dis. 2014 Oct 15;59(8):1198-9. doi: 10.1093/cid/ciu561. Epub 2014 Jul 30. Clin Infect Dis. 2014. PMID: 25077788 Free PMC article. No abstract available.
  • Diagnostic value of eosinopenia in non-Typhi Salmonella enteritis.
    Farmakiotis D, Ntouloulis C, Mihailidis N, Theofilogiannakos EK, Makavos G, Bakas A, Vassiliadou E. Farmakiotis D, et al. Clin Infect Dis. 2014 Oct 15;59(8):1197-8. doi: 10.1093/cid/ciu557. Epub 2014 Jul 30. Clin Infect Dis. 2014. PMID: 25077789 No abstract available.

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