Evaluation of the Clinical and Microbiological Response to Salmonella Paratyphi A Infection in the First Paratyphoid Human Challenge Model.
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.



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.



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.



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.



NCT02100397.
Oxford Vaccine Group, Department of Paediatrics, University of Oxford, and the National Institute for Health Research Oxford Biomedical Research Centre, Oxford, UK.
Hazel C
HC
Dobinson
Oxford Vaccine Group, Department of Paediatrics, University of Oxford, and the National Institute for Health Research Oxford Biomedical Research Centre, Oxford, UK.
Malick M
MM
Gibani
Oxford Vaccine Group, Department of Paediatrics, University of Oxford, and the National Institute for Health Research Oxford Biomedical Research Centre, Oxford, UK.
Claire
C
Jones
Oxford Vaccine Group, Department of Paediatrics, University of Oxford, and the National Institute for Health Research Oxford Biomedical Research Centre, Oxford, UK.
Helena B
HB
Thomaides-Brears
Oxford Vaccine Group, Department of Paediatrics, University of Oxford, and the National Institute for Health Research Oxford Biomedical Research Centre, Oxford, UK.|Nuffield Department of Primary Care Health Sciences, University of Oxford, United Kingdom.
Merryn
M
Voysey
Oxford Vaccine Group, Department of Paediatrics, University of Oxford, and the National Institute for Health Research Oxford Biomedical Research Centre, Oxford, UK.
Thomas C
TC
Darton
Oxford Vaccine Group, Department of Paediatrics, University of Oxford, and the National Institute for Health Research Oxford Biomedical Research Centre, Oxford, UK.
Claire S
CS
Waddington
Oxford Vaccine Group, Department of Paediatrics, University of Oxford, and the National Institute for Health Research Oxford Biomedical Research Centre, Oxford, UK.
Danielle
D
Campbell
Oxford Vaccine Group, Department of Paediatrics, University of Oxford, and the National Institute for Health Research Oxford Biomedical Research Centre, Oxford, UK.
Iain
I
Milligan
Oxford Vaccine Group, Department of Paediatrics, University of Oxford, and the National Institute for Health Research Oxford Biomedical Research Centre, Oxford, UK.
Liqing
L
Zhou
Oxford Vaccine Group, Department of Paediatrics, University of Oxford, and the National Institute for Health Research Oxford Biomedical Research Centre, Oxford, UK.
Sonu
S
Shrestha
Oxford Vaccine Group, Department of Paediatrics, University of Oxford, and the National Institute for Health Research Oxford Biomedical Research Centre, Oxford, UK.
Simon A
SA
Kerridge
Oxford Vaccine Group, Department of Paediatrics, University of Oxford, and the National Institute for Health Research Oxford Biomedical Research Centre, Oxford, UK.
Anna
A
Peters
Oxford Vaccine Group, Department of Paediatrics, University of Oxford, and the National Institute for Health Research Oxford Biomedical Research Centre, Oxford, UK.
Zoe
Z
Stevens
GSK Vaccines Institute for Global Health, Siena, Italy.
Audino
A
Podda
GSK Vaccines Institute for Global Health, Siena, Italy.
Laura B
LB
Martin
European Vaccine Initiative, Heidelberg, Germany.
Flavia
F
D'Alessio
Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.
Duy Pham
DP
Thanh
Oxford University Clinical Research Unit, Patan Academy of Health Sciences, Kathmandu, Nepal.
Buddha
B
Basnyat
Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.|Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, UK.|London School of Hygiene and Tropical Medicine, London, UK.
Stephen
S
Baker
Nuffield Department of Medicine, University of Oxford, United Kingdom.
Brian
B
Angus
Center for Vaccine Development, University of Maryland School of Medicine, Baltimore.
Myron M
MM
Levine
Oxford Vaccine Group, Department of Paediatrics, University of Oxford, and the National Institute for Health Research Oxford Biomedical Research Centre, Oxford, UK.
Christoph J
CJ
Blohmke
Oxford Vaccine Group, Department of Paediatrics, University of Oxford, and the National Institute for Health Research Oxford Biomedical Research Centre, Oxford, UK.
Andrew J
AJ
Pollard
D000328:Adult; D016470:Bacteremia / Q000382:microbiology* / Q000473:pathology*; D001769:Blood / Q000382:microbiology; D005243:Feces / Q000382:microbiology; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D010284:Paratyphoid Fever / Q000382:microbiology* / Q000473:pathology*; D012482:Salmonella paratyphi A / Q000302:isolation & purification*; D013696:Temperature; D013997:Time Factors; D055815:Young Adult
Salmonella enterica paratyphi A; enteric fever; human challenge study; immune responses; paratyphoid infection