Controlled Human Infection for Vaccination Against Streptococcus Pyogenes

NCT03361163 | Completed Phase 1 DMC

• 1 other identifier: CHIVAS-M75
• Study Type: interventional
• Target: 25
• Locations: 1 country
• Sites: 1

Brief Summary

Group A Streptococcus (GAS) infection is a major cause of death and disability globally with a disproportionately high burden in settings of disadvantage worldwide. Acute infections due to GAS range from very common superficial skin infections (\>150 million prevalent cases) and pharyngitis (over 600 million incident cases) to life-threatening invasive disease (\>600,000 incident cases) such as necrotising fasciitis. Post-infectious GAS sequelae of GAS include acute rheumatic fever (ARF, \~500,000 incident cases) leading to rheumatic heart disease (RHD, \~34 million prevalent cases), and acute glomerulonephritis. The health services impact of GAS disease in all its forms is immense and strikes at every level from primary to intensive care. Controlled human infection models (CHIMs) have a long history of critical contributions to vaccine development. Data from CHIMs meeting modern scientific, regulatory, and ethical standards, are aiding efforts to control over 25 major human pathogens, including bacteria (e.g. pneumococcus, cholera), viruses (e.g. respiratory syncytial virus, influenza), and parasites (e.g. malaria, schistosomiasis). A reliable and safe controlled human infection model of GAS pharyngitis will be an important part of the global vaccine development effort. To build the model, the investigators are undertaking a dose-ranging study using an observational, dose-escalation, inpatient trial to determine the dose of GAS administered by direct oropharyngeal inoculation (bacteria 'painted' onto throat) required to reliably produce a pharyngitis attack rate of ≥ 60% in carefully screened healthy adult volunteers.

Conditions

Streptococcus Pyogenes Pharyngitis; Streptococcus Pharyngitis; Strep Throat; Streptococcus Pyogenes Infection; Group A Streptococcus: B Hemolytic Pharyngitis; Group A Streptococcal Infection; Gram-Positive Bacterial Infections; Bacterial Infections

Keywords

Streptococcus pyogenes pharyngitis; Streptococcus Pharyngitis; Strep Throat; Streptococcus pyogenes Infection; Group A Streptococcus: B Hemolytic Pharyngitis; Group A Streptococcal Infection; Controlled human infection model; Challenge study

Outcome Measures

Primary Outcomes (1)

• Proportion of participants at each GAS M75 dose level meeting the study pharyngitis endpoint

  Proportion of participants at each GAS M75 dose level who develop pharyngitis, using a combined clinical-microbiological definition comprising sore throat, physical examination signs of pharyngitis and tonsillitis, and microbiological confirmation of GAS by culture and nucleic acid amplification test of throat swabs.

  Up to 6 days after challenge dose administered.

Study Arms (1)

GAS oropharyngeal challenge

EXPERIMENTAL

Biological: emm75 Streptococcus pyogenes (GAS M75, strain 611024) Direct oropharyngeal application using a sterile-tipped Dacron swab after immersion for 10 seconds in a 1mL vial containing 1-3x10\^4 to 1-3x10\^8 colony forming units (CFU) of the challenge strain (depending on dose group allocation).

Biological: emm75 Streptococcus pyogenes (GAS M75, strain 611024)

Interventions

emm75 Streptococcus pyogenes (GAS M75, strain 611024) BIOLOGICAL

Direct oropharyngeal application by swab following immersion in a solution containing a specified concentration (dose) of GAS M75.

Also known as: GAS M75, Group A Streptococcus challenge inoculum

GAS oropharyngeal challenge

Eligibility Criteria

• Age: 18 Years - 40 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Males or females, aged 18 - 40 years (inclusive) on the day of informed consent.
• Medically healthy, determined by medical history, physical examination, transthoracic echocardiogram, non-clinically significant laboratory profiles, vital signs, and 12-lead ECG at screening, as deemed by the investigator.
• No active or chronic diseases/disorders, no history of hospitalisation for illness within the six months prior to enrolment into study, and no major surgery within the 12 months prior to enrolment into study.
• Body mass index of 18.0 - 32.0 kg/m2 and body weight ≥ 50.0kg
• Systolic blood pressure (SBP) of 90 mmHg - 140 mmHg and diastolic blood pressure (DBP) of 50 mmHg - 90 mmHg. Vital signs can be repeated up to two times.
• Resting heart rate (HR), as measured by ECG of 40bpm - 100 bpm (confirmed by one repeat at screening).
• Females must be non-pregnant, non-lactating or postmenopausal for at least 1 year (as confirmed by follicle-stimulating hormone \[FSH\]), or surgically sterile for at least 6 months prior to dosing.
• All male and females of childbearing potential must agree to use two forms of acceptable contraception from the time of signing informed consent until 30 days after final dose of rifampicin.
• Acceptable forms of contraception include: barrier method (eg. condom, diaphragm); pharmacological hormonal methods (oral contraceptive pill, long-acting implantable, intrauterine device).
• Rifampicin may reduce the activity of oral and implantable contraceptives (not intrauterine devices) so additional use of a barrier method is required for 30 days after the final dose of rifampicin for participants using these methods.
• Participants who abstain from penile-vaginal intercourse are eligible when this is their preferred and usual lifestyle. These participants must not be planning in vitro fertilization within the study and follow-up period.
• Must be willing and able to read, understand, and sign the participant information and consent form.
• Able and willing (in the Investigator's opinion) to comply with all study requirements, including the in-patient confinement period and outpatient visits for the duration of the study (approximately 6 months including follow-up visits).

You may not qualify if:

• History of any clinically important cardiac, endocrinologic, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic, dermatologic, psychiatric, and renal, or other major disease, as determined by the Investigator.
• History of tonsillectomy, adenoidectomy or splenectomy.
• Known or suspected autoimmune disease or impairment/alteration of immune function resulting from:
• Congenital or acquired immunodeficiency (including immunoglobulin A deficiency)
• Receipt of immunosuppressive therapy such as anti-cancer chemotherapy or radiation therapy within the preceding 6 months.
• Presence or history of a severe drug hypersensitivity, or allergic disease diagnosed and treated by a physician or history of a severe allergic reaction, anaphylaxis or convulsions following any vaccination or infusion.
• Personal or family history of severe GAS infection or sequelae (such as acute rheumatic fever, rheumatic heart disease, post-streptococcal glomerulonephritis) or invasive GAS disease (toxic shock syndrome, necrotizing fasciitis, bloodstream infection, pleural empyema, meningitis).
• Clinically significant disease or any condition or disease that might affect drug absorption, distribution or excretion, e.g. gastrectomy, diarrhea.
• Any vaccination within the last 28 days or use of any antibiotic therapy during the 14 days before challenge.
• Presence of acute infectious disease or febrile illness (e.g., sub-lingual temperature ≥ 38.5°C) within the five days prior to inoculation.
• Significant acute or chronic infection within 14 days prior to inoculation that the Investigator deems may compromise participant safety.
• Any clinically significant abnormal finding on biochemistry or haematology blood tests, urine analysis, ECG or transthoracic echocardiogram.
• Positive serologic results for human immunodeficiency virus (HIV) antibodies, hepatitis B surface antigen (HBsAg), and/or hepatitis C virus (HCV) antibodies.
• Ex-smoker with a \>10 pack year smoking history or a current smoker who is unable to stop smoking for the duration of the study
• History or presence of alcohol abuse (defined as regular alcohol consumption of more than 40g per day) or drug habituation, or any prior intravenous usage of an illicit substance.

Sponsors & Collaborators

• Andrew Steer: lead
• University of Melbourne: collaborator
• Nucleus Network Ltd: collaborator
• National Health and Medical Research Council, Australia: collaborator
• Telethon Kids Institute: collaborator
• The Peter Doherty Institute for Infection and Immunity: collaborator
• Queen Fabiola Children's University Hospital: collaborator
• Griffith University: collaborator
• University of Wollongong: collaborator
• The University of Queensland: collaborator
• University of Auckland, New Zealand: collaborator
• University of Tennessee: collaborator

Study Sites (1)

Centre for Clinical Studies (Nucleus Network Limited)

Melbourne, Victoria, 3004, Australia

Location

Related Publications (3)

• Osowicki J, Azzopardi KI, Fabri L, Frost HR, Rivera-Hernandez T, Neeland MR, Whitcombe AL, Grobler A, Gutman SJ, Baker C, Wong JMF, Lickliter JD, Waddington CS, Pandey M, Schuster T, Cheng AC, Pollard AJ, McCarthy JS, Good MF, Dale JB, Batzloff M, Moreland NJ, Walker MJ, Carapetis JR, Smeesters PR, Steer AC. A controlled human infection model of Streptococcus pyogenes pharyngitis (CHIVAS-M75): an observational, dose-finding study. Lancet Microbe. 2021 Jul;2(7):e291-e299. doi: 10.1016/S2666-5247(20)30240-8. Epub 2021 Apr 15.

  PMID: 35544165 DERIVED

• Fabri LV, Azzopardi KI, Osowicki J, Frost HR, Smeesters PR, Steer AC. An emm-type specific qPCR to track bacterial load during experimental human Streptococcus pyogenes pharyngitis. BMC Infect Dis. 2021 May 21;21(1):463. doi: 10.1186/s12879-021-06173-w.

  PMID: 34020607 DERIVED

• Osowicki J, Azzopardi KI, Baker C, Waddington CS, Pandey M, Schuster T, Grobler A, Cheng AC, Pollard AJ, McCarthy JS, Good MF, Walker MJ, Dale JB, Batzloff MR, Carapetis JR, Smeesters PR, Steer AC. Controlled human infection for vaccination against Streptococcus pyogenes (CHIVAS): Establishing a group A Streptococcus pharyngitis human infection study. Vaccine. 2019 Jun 6;37(26):3485-3494. doi: 10.1016/j.vaccine.2019.03.059. Epub 2019 May 14.

  PMID: 31101422 DERIVED

MeSH Terms

Conditions

Streptococcal Infections; Gram-Positive Bacterial Infections; Bacterial Infections

Condition Hierarchy (Ancestors)

Bacterial Infections and Mycoses; Infections

Study Officials

• Janet Wong, MBBS,BSc

  Senior Medical Officer, Nucleus Network Limited

  PRINCIPAL INVESTIGATOR

• Andrew C Steer, MBBS,MPH,PhD

  Group A Streptococcal Research Group, Murdoch Children's Research Institute

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor, Group A Streptococcal Research Group Leader

Model Details: Observational, sequential, dose-escalation

Study Record Dates

• First Submitted: November 14, 2017
• First Posted: December 4, 2017
• Study Start: July 10, 2018
• Primary Completion: September 28, 2019
• Study Completion: April 21, 2020
• Last Updated: May 19, 2020

Record last verified: 2020-05

Data Sharing

• IPD Sharing: Will not share

Locations

AU (1)