Details

Autor(en) / Beteiligte

• Osowicki, Joshua
• Azzopardi, Kristy I
• Fabri, Loraine
• Frost, Hannah R
• Rivera-Hernandez, Tania
• Neeland, Melanie R
• Whitcombe, Alana L
• Grobler, Anneke
• Gutman, Sarah J
• Baker, Ciara
• Wong, Janet M F
• Lickliter, Jason D
• Waddington, Claire S
• Pandey, Manisha
• Schuster, Tibor
• Cheng, Allen C
• Pollard, Andrew J
• McCarthy, James S
• Good, Michael F
• Dale, James B
• Batzloff, Michael
• Moreland, Nicole J
• Walker, Mark J
• Carapetis, Jonathan R
• Smeesters, Pierre R
• Steer, Andrew C

Titel

A controlled human infection model of Streptococcus pyogenes pharyngitis (CHIVAS-M75): an observational, dose-finding study

Ist Teil von

• The Lancet. Microbe, 2021-07, Vol.2 (7), p.e291-e299

Ort / Verlag

England: Elsevier Ltd

Erscheinungsjahr

2021

Quelle

MEDLINE

Beschreibungen/Notizen

• Streptococcus pyogenes is a leading cause of infection-related morbidity and mortality. A reinvigorated vaccine development effort calls for new clinically relevant human S pyogenes experimental infection models to support proof of concept evaluation of candidate vaccines. We describe the initial Controlled Human Infection for Vaccination Against S pyogenes (CHIVAS-M75) study, in which we aimed to identify a dose of emm75 S pyogenes that causes acute pharyngitis in at least 60% of volunteers when applied to the pharynx by swab. This observational, dose-finding study was done in a clinical trials facility in Melbourne (VIC, Australia). Groups of healthy volunteers aged 18–40 years, at low risk of complicated S pyogenes disease, and without high type-specific anti-emm75 IgG antibodies against the challenge strain were challenged and closely monitored as inpatients for up to 6 days, and then as outpatients for 6 months. Antibiotics were started upon diagnosis (clinical signs and symptoms of pharyngitis and a positive rapid molecular test) or after 5 days in those without pharyngitis. Rapid test results were confirmed by standard bacterial culture. After a sentinel participant, cohorts of five and then ten participants were challenged, with protocol-directed dose-escalation or de-escalation for subsequent cohorts. The primary outcome was the proportion of participants at each dose level with pharyngitis by day 5 after challenge. The study is registered with ClinicalTrials.gov, NCT03361163. Between July 10, 2018, and Sept 23, 2019, 25 healthy adults were challenged with emm75 S pyogenes and included in analyses. Pharyngitis was diagnosed in 17 (85%; 95% CI 62–97) of 20 participants at the starting dose level (1–3 × 105 colony-forming units [CFU]/mL). This high proportion prompted dose de-escalation. At the lower dose level (1–3 × 104 CFU/mL), pharyngitis was diagnosed in one of five participants. Immunological, biochemical, and microbiological results supported the clinical picture, with acute symptomatic pharyngitis characterised by pharyngeal colonisation by S pyogenes accompanied by significantly elevated C-reactive protein and inflammatory cytokines (eg, interferon-γ and interleukin-6), and modest serological responses to streptolysin O and deoxyribonuclease B. There were no severe (grade 3) or serious adverse events related to challenge. We have established a reliable pharyngitis human infection model with reassuring early safety findings to accelerate development of vaccines and other interventions to control disease due to S pyogenes. Australian National Health and Medical Research Council.