A controlled human infection model of Streptococcus pyogenes pharyngitis (CHIVAS-M75): an observational, dose-finding
Joshua Osowicki1, Kristy I Azzopardi2, Loraine Fabri3
1Tropical Diseases Research Group, Murdoch Children's Research Institute, Melbourne, VIC, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia; Infectious Diseases Unit, Department of General Medicine, Royal Children's Hospital Melbourne, Melbourne, VIC, Australia.
Background:
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.
Methods:
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.
Findings:
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.
Interpretation:
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.
Funding:
Australian National Health and Medical Research Council.
Insights
A new human infection model for Streptococcus pyogenes pharyngitis was established. This model shows early safety and can accelerate vaccine development against S. pyogenes infections.
Area of Science:
- Infectious Diseases
- Vaccinology
- Clinical Microbiology
Background:
- Streptococcus pyogenes is a major cause of morbidity and mortality.
- Development of effective vaccines against S. pyogenes is a public health priority.
- Clinically relevant human experimental infection models are needed for vaccine evaluation.
Purpose of the Study:
- To establish a human experimental infection model for Streptococcus pyogenes (S. pyogenes) pharyngitis.
- To identify a safe and effective dose of emm75 S. pyogenes for inducing pharyngitis in volunteers.
- To support the development of novel vaccines and interventions against S. pyogenes.
Main Methods:
- An observational, dose-finding study (CHIVAS-M75) was conducted with healthy volunteers.
- Volunteers were challenged with varying doses of emm75 S. pyogenes via pharyngeal swab.
- Participants were monitored for clinical signs of pharyngitis and confirmed by rapid molecular tests and bacterial culture.
Main Results:
- Pharyngitis was diagnosed in 85% of participants at the initial dose (1-3 × 10^5 CFU/mL).
- Dose de-escalation was performed, with one case of pharyngitis at the lower dose (1-3 × 10^4 CFU/mL).
- Infection was characterized by pharyngeal colonization, elevated inflammatory markers, and modest serological responses. No severe adverse events were reported.
Conclusions:
- A reliable human experimental infection model for S. pyogenes pharyngitis has been established.
- The model demonstrates reassuring early safety findings.
- This model will accelerate the development of vaccines and other interventions for S. pyogenes infections.
