Journal
CLINICAL INFECTIOUS DISEASES
Volume 64, Issue 8, Pages 1066-1073Publisher
OXFORD UNIV PRESS INC
DOI: 10.1093/cid/cix042
Keywords
paratyphoid infection; enteric fever; Salmonella enterica paratyphi A; human challenge study; immune responses
Categories
Funding
- Bill & Melinda Gates Foundation [OPP1084259]
- European Vaccine Initiative [PIM]
- Wellcome Trust Strategic Translational Award [092661]
- National Institute for Health Research Clinical Research Network
- Wellcome Trust
- National Institute for Health Research Oxford Biomedical Research Centre
- European Union
- National Institute for Health Research [CL-2014-04-001] Funding Source: researchfish
- Bill and Melinda Gates Foundation [OPP1084259] Funding Source: Bill and Melinda Gates Foundation
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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 x 10(3) colony-forming units [CFU] and group 2: 0.5-1 x 10(3) 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 degrees C for >= 12 hours and/or bacteremia) or at day 14 postchallenge. Results. The primary study objective was achieved following challenge with 1-5 x 10(3) 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 x 10(3) 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.
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