Evaluation of the clinical and microbiological response to salmonella paratyphi a infection in the first paratyphoid human challenge model
Author(s)
Type
Journal Article
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.
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.
Date Issued
2017-04-15
Date Acceptance
2017-02-01
Citation
Clinical Infectious Diseases, 2017, 64 (8), pp.1066-1073
ISSN
1058-4838
Publisher
Oxford University Press (OUP)
Start Page
1066
End Page
1073
Journal / Book Title
Clinical Infectious Diseases
Volume
64
Issue
8
Copyright Statement
© 2017 The Author. 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.
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.
Identifier
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000397809800010&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Subjects
Science & Technology
Life Sciences & Biomedicine
Immunology
Infectious Diseases
Microbiology
paratyphoid infection
enteric fever
Salmonella enterica paratyphi A
human challenge study
immune responses
ENTERICA SEROVAR PARATYPHI
ORAL TYPHOID VACCINE
FEVER
OUTPATIENT
DESIGN
BURDEN
Publication Status
Published
Date Publish Online
2017-02-04