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

Background: To expedite the evaluation of vaccines against paratyphoid fever, we aimed to develop the first human challenge model of S. Paratyphi A infection. Methods: Two groups of 20 participants underwent oral challenge with S. Paratyphi A following sodium bicarbonate pre-treatment at one of two dose levels (Group 1: 1-5 x 103 CFU and Group 2: 0.5-1 x 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 pre-specified diagnostic criteria were met (temperature ≥38°C for ≥12 hours and/or bacteraemia) or at day 14 post challenge. Results: The primary study objective was achieved following challenge with 1-5 x 103 CFU (Group 1), which resulted in an attack rate of 12/20 (60%). Compared with typhoid challenge, paratyphoid was notable for high rates of subclinical bacteraemia (at this dose 11/20; 55%). Despite limited symptoms, bacteraemia persisted for up to 96 hours after antibiotic treatment (median duration of bacteraemia 53hrs; IQR 24-85hrs). Shedding of S. Paratyphi A in stool typically preceded onset of bacteraemia. Conclusions: Challenge with S. Paratyphi A at a dose of 1-5 x 103 CFU was well tolerated and associated with an acceptable safety profile. The frequency and persistence of bacteraemia 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 bacteraemia and/or symptomatology. Clinicaltrials.gov Registration: NCT02100397