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Evaluation of the clinical and microbiological response to Salmonella Paratyphi A infection in the first paratyphoid human challenge model

Dobinson, HC; Gibani, MM; Jones, C; Thomaides-Brears, HB; Voysey, M; Darton, TC; Waddington, CS; Campbell, D; Milligan, I; Zhou, L; et al. Dobinson, HC; Gibani, MM; Jones, C; Thomaides-Brears, HB; Voysey, M; Darton, TC; Waddington, CS; Campbell, D; Milligan, I; Zhou, L; Shrestha, S; Kerridge, SA; Peters, A; Stevens, Z; Podda, A; Martin, LB; D’Alessio, F; Thanh, DP; Basnyat, B; Baker, S; Angus, B; Levine, MM; Blohmke, CJ; Pollard, AJ (2017) Evaluation of the clinical and microbiological response to Salmonella Paratyphi A infection in the first paratyphoid human challenge model. Clinical Infectious Diseases, 64 (8). pp. 1066-1073. ISSN 1058-4838 https://doi.org/10.1093/cid/cix042
SGUL Authors: Zhou, Li Qing

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Abstract

Background. To expedite the evaluation of vaccines against paratyphoid fever, we aimed to develop the first human challenge model of Salmonella enterica serovar Paratyphi A infection. Methods. Two groups of 20 participants underwent oral challenge with S. Paratyphi A following sodium bicarbonate pretreatment at 1 of 2 dose levels (group 1: 1–5 × 103 colony-forming units [CFU] and group 2: 0.5–1 × 103 CFU). Participants were monitored in an outpatient setting with daily clinical review and collection of blood and stool cultures. Antibiotic treatment was started when prespecified diagnostic criteria were met (temperature ≥38°C for ≥12 hours and/or bacteremia) or at day 14 postchallenge. Results. The primary study objective was achieved following challenge with 1–5 × 103 CFU (group 1), which resulted in an attack rate of 12 of 20 (60%). Compared with typhoid challenge, paratyphoid was notable for high rates of subclinical bacteremia (at this dose, 11/20 [55%]). Despite limited symptoms, bacteremia persisted for up to 96 hours after antibiotic treatment (median duration of bacteremia, 53 hours [interquartile range, 24–85 hours]). Shedding of S. Paratyphi A in stool typically preceded onset of bacteremia. Conclusions. Challenge with S. Paratyphi A at a dose of 1–5 × 103 CFU was well tolerated and associated with an acceptable safety profile. The frequency and persistence of bacteremia in the absence of clinical symptoms was notable, and markedly different from that seen in previous typhoid challenge studies. We conclude that the paratyphoid challenge model is suitable for the assessment of vaccine efficacy using endpoints that include bacteremia and/or symptomatology. Clinical Trials Registration. NCT02100397.

Item Type: Article
Additional Information: © The Author 2017. Published by Oxford University Press for 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/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: Microbiology, 06 Biological Sciences, 11 Medical And Health Sciences
SGUL Research Institute / Research Centre: Academic Structure > Infection and Immunity Research Institute (INII)
Journal or Publication Title: Clinical Infectious Diseases
ISSN: 1058-4838
Dates:
DateEvent
15 April 2017Published
4 February 2017Published Online
10 January 2017Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
PIMthe European Vaccine InitiativeUNSPECIFIED
OPP1084259The Bill and Melinda Gates FoundationUNSPECIFIED
092661Wellcome Trust Strategic Translational AwardUNSPECIFIED
URI: http://openaccess.sgul.ac.uk/id/eprint/108555
Publisher's version: https://doi.org/10.1093/cid/cix042

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