A controlled human infection model of Streptococcus pyogenes pharyngitis (CHIVAS-M75): an observational, dose-finding study
Summary: 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 d...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2021-07-01
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| Series: | The Lancet Microbe |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2666524720302408 |
| _version_ | 1819154974219698176 |
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| author | Joshua Osowicki, MBBS Kristy I Azzopardi, BSc Loraine Fabri, MD Hannah R Frost, PhD Tania Rivera-Hernandez, PhD Melanie R Neeland, PhD Alana L Whitcombe, BSc Anneke Grobler, PhD Sarah J Gutman, MBBS Ciara Baker, MSc Janet M F Wong, MBBS Jason D Lickliter, PhD Claire S Waddington, PhD Manisha Pandey, PhD Tibor Schuster, PhD Allen C Cheng, ProfPhD Andrew J Pollard, ProfPhD James S McCarthy, ProfMD Michael F Good, ProfPhD James B Dale, ProfMD Michael Batzloff, PhD Nicole J Moreland, PhD Mark J Walker, ProfPhD Jonathan R Carapetis, ProfPhD Pierre R Smeesters, ProfPhD Andrew C Steer, ProfPhD |
| author_facet | Joshua Osowicki, MBBS Kristy I Azzopardi, BSc Loraine Fabri, MD Hannah R Frost, PhD Tania Rivera-Hernandez, PhD Melanie R Neeland, PhD Alana L Whitcombe, BSc Anneke Grobler, PhD Sarah J Gutman, MBBS Ciara Baker, MSc Janet M F Wong, MBBS Jason D Lickliter, PhD Claire S Waddington, PhD Manisha Pandey, PhD Tibor Schuster, PhD Allen C Cheng, ProfPhD Andrew J Pollard, ProfPhD James S McCarthy, ProfMD Michael F Good, ProfPhD James B Dale, ProfMD Michael Batzloff, PhD Nicole J Moreland, PhD Mark J Walker, ProfPhD Jonathan R Carapetis, ProfPhD Pierre R Smeesters, ProfPhD Andrew C Steer, ProfPhD |
| author_sort | Joshua Osowicki, MBBS |
| collection | DOAJ |
| description | Summary: 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. |
| first_indexed | 2024-12-22T15:29:36Z |
| format | Article |
| id | doaj.art-ec41c56b2f5e46caa2cee686d70a813b |
| institution | Directory Open Access Journal |
| issn | 2666-5247 |
| language | English |
| last_indexed | 2024-12-22T15:29:36Z |
| publishDate | 2021-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | The Lancet Microbe |
| spelling | doaj.art-ec41c56b2f5e46caa2cee686d70a813b2022-12-21T18:21:24ZengElsevierThe Lancet Microbe2666-52472021-07-0127e291e299A controlled human infection model of Streptococcus pyogenes pharyngitis (CHIVAS-M75): an observational, dose-finding studyJoshua Osowicki, MBBS0Kristy I Azzopardi, BSc1Loraine Fabri, MD2Hannah R Frost, PhD3Tania Rivera-Hernandez, PhD4Melanie R Neeland, PhD5Alana L Whitcombe, BSc6Anneke Grobler, PhD7Sarah J Gutman, MBBS8Ciara Baker, MSc9Janet M F Wong, MBBS10Jason D Lickliter, PhD11Claire S Waddington, PhD12Manisha Pandey, PhD13Tibor Schuster, PhD14Allen C Cheng, ProfPhD15Andrew J Pollard, ProfPhD16James S McCarthy, ProfMD17Michael F Good, ProfPhD18James B Dale, ProfMD19Michael Batzloff, PhD20Nicole J Moreland, PhD21Mark J Walker, ProfPhD22Jonathan R Carapetis, ProfPhD23Pierre R Smeesters, ProfPhD24Andrew C Steer, ProfPhD25Tropical 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; Correspondence to: Dr Joshua Osowicki, Tropical Diseases Research Group, Murdoch Children's Research Institute, Melbourne, 3052 VIC, AustraliaTropical Diseases Research Group, Murdoch Children's Research Institute, Melbourne, VIC, AustraliaTropical Diseases Research Group, Murdoch Children's Research Institute, Melbourne, VIC, Australia; Paediatric Department, Academic Children Hospital Queen Fabiola, Université Libre de Bruxelles, Brussels, BelgiumTropical Diseases Research Group, Murdoch Children's Research Institute, Melbourne, VIC, AustraliaUnidad de Investigación Médica en Inmunoquímica, Hospital de Especialidades del Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City, Mexico; School of Chemistry and Molecular Biosciences and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD, AustraliaEpigenetics Research Group, Murdoch Children's Research Institute, Melbourne, VIC, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC, AustraliaDepartment of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New ZealandClinical Epidemiology and Biostatistics Unit, Murdoch Children's Research Institute, Melbourne, VIC, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC, AustraliaDepartment of Cardiology, The Alfred Hospital, Melbourne, VIC, Australia; Imaging Research, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia; Department of Medicine, Nursing and Health Sciences, Monash University, Melbourne, VIC, AustraliaTropical Diseases Research Group, Murdoch Children's Research Institute, Melbourne, VIC, AustraliaNucleus Network, Melbourne, VIC, AustraliaNucleus Network, Melbourne, VIC, AustraliaDepartment of Medicine, University of Cambridge, Cambridge, UK; Wesfarmers Centre for Vaccines and Infectious Diseases, Telethon Kids Institute, University of Western Australia, Perth, WA, AustraliaThe Institute for Glycomics, Griffith University, Gold Coast, QLD, AustraliaClinical Epidemiology and Biostatistics Unit, Murdoch Children's Research Institute, Melbourne, VIC, Australia; Department of Family Medicine, McGill University, Montreal, QC, CanadaInfection Prevention and Healthcare Epidemiology Unit, The Alfred Hospital, Melbourne, VIC, Australia; School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, AustraliaOxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK; National Institute for Health Research, Oxford Biomedical Research Centre, Oxford, UKSchool of Medicine, The University of Queensland, Brisbane, QLD, Australia; QIMR Berghofer Medical Research Institute, Brisbane, QLD, AustraliaThe Institute for Glycomics, Griffith University, Gold Coast, QLD, AustraliaDepartment of Medicine, University of Tennessee Health Science Center, Memphis, TN, USAThe Institute for Glycomics, Griffith University, Gold Coast, QLD, AustraliaDepartment of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New ZealandSchool of Chemistry and Molecular Biosciences and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD, AustraliaWesfarmers Centre for Vaccines and Infectious Diseases, Telethon Kids Institute, University of Western Australia, Perth, WA, Australia; Faculty of Health and Medical Sciences, University of Western Australia, Perth, WA, Australia; Tropical Diseases Research Group, Murdoch Children's Research Institute, Melbourne, VIC, Australia; Department of Paediatric Infectious Diseases, Perth Children's Hospital, Perth, WA, AustraliaTropical Diseases Research Group, Murdoch Children's Research Institute, Melbourne, VIC, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia; Paediatric Department, Academic Children Hospital Queen Fabiola, Université Libre de Bruxelles, Brussels, Belgium; Molecular Bacteriology Laboratory, Université Libre de Bruxelles, Brussels, BelgiumTropical 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, AustraliaSummary: 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.http://www.sciencedirect.com/science/article/pii/S2666524720302408 |
| spellingShingle | Joshua Osowicki, MBBS Kristy I Azzopardi, BSc Loraine Fabri, MD Hannah R Frost, PhD Tania Rivera-Hernandez, PhD Melanie R Neeland, PhD Alana L Whitcombe, BSc Anneke Grobler, PhD Sarah J Gutman, MBBS Ciara Baker, MSc Janet M F Wong, MBBS Jason D Lickliter, PhD Claire S Waddington, PhD Manisha Pandey, PhD Tibor Schuster, PhD Allen C Cheng, ProfPhD Andrew J Pollard, ProfPhD James S McCarthy, ProfMD Michael F Good, ProfPhD James B Dale, ProfMD Michael Batzloff, PhD Nicole J Moreland, PhD Mark J Walker, ProfPhD Jonathan R Carapetis, ProfPhD Pierre R Smeesters, ProfPhD Andrew C Steer, ProfPhD A controlled human infection model of Streptococcus pyogenes pharyngitis (CHIVAS-M75): an observational, dose-finding study The Lancet Microbe |
| title | A controlled human infection model of Streptococcus pyogenes pharyngitis (CHIVAS-M75): an observational, dose-finding study |
| title_full | A controlled human infection model of Streptococcus pyogenes pharyngitis (CHIVAS-M75): an observational, dose-finding study |
| title_fullStr | A controlled human infection model of Streptococcus pyogenes pharyngitis (CHIVAS-M75): an observational, dose-finding study |
| title_full_unstemmed | A controlled human infection model of Streptococcus pyogenes pharyngitis (CHIVAS-M75): an observational, dose-finding study |
| title_short | A controlled human infection model of Streptococcus pyogenes pharyngitis (CHIVAS-M75): an observational, dose-finding study |
| title_sort | controlled human infection model of streptococcus pyogenes pharyngitis chivas m75 an observational dose finding study |
| url | http://www.sciencedirect.com/science/article/pii/S2666524720302408 |
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