Controlled Human Infection for Vaccination Against Streptococcus Pyogenes (CHIVAS)
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|ClinicalTrials.gov Identifier: NCT03361163|
Recruitment Status : Recruiting
First Posted : December 4, 2017
Last Update Posted : August 14, 2019
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.
|Condition or disease||Intervention/treatment||Phase|
|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||Biological: emm75 Streptococcus pyogenes (GAS M75, strain 611024)||Phase 1|
Group A Streptococcus (GAS) is a ubiquitous human pathogen. Its impact begins in early childhood and is felt most by those who have the least. Globally, the health services impact of GAS disease in all its forms is immense and strikes at every level from primary to intensive care. Despite recognition of the need for GAS vaccine development, there are major obstacles impeding progress. A human challenge model promises to help to shift inertia in GAS vaccine development.
The objective of this study is to use an observational, dose-escalation, inpatient trial to determine the dose of GAS administered by direct oropharyngeal inoculation required to reliably produce a pharyngitis attack rate of ≥ 60% in carefully screened healthy adult volunteers. A GAS strain has been specially selected and prepared for this study to ensure safety and clinical relevance. Potential participants aged 18 to 40 years, the age range associated with the lowest risk of invasive GAS disease, will be carefully screened to minimise risk and maximise the likelihood of achieving the pharyngitis endpoint.
The results of three human GAS pharyngeal vaccine-challenge studies from the 1970s are encouraging, and reassuring. GAS challenge did cause pharyngitis and was safe, with all participants responding to antibiotics and none experiencing complications, despite these studies using more aggressive GAS strains.
The study design involves direct oropharyngeal inoculation of GAS to sequential cohorts. Up to four doses will be tested, from 1-3 x 10^5 cfu/mL (lower than previous GAS challenge studies) to a maximum of 1-3 x 10^8 cfu/mL. A minimum of 20 and maximum of 80 participants will be challenged. The challenge procedure aligns closely that used successfully in the 1970s GAS human challenge studies. An incubation period of 36 to 72 hours is expected before onset of symptoms. Participants will be intensively monitored inpatients for up to six days after challenge. The primary outcome measure is GAS pharyngitis, as defined by a combination of positive clinical and laboratory features. All participants developing pharyngitis will be treated with antibiotics and and those without pharyngitis will also be treated after 5 days. Participants will be followed as outpatients at 1 week, and 1, 3, and 6 months after discharge.
*Due to an unexpectedly very high proportion of participants developing pharyngitis at the starting dose, scope for dose de-escalation was subsequently included in a protocol amendment, using a dose of 1-3 x 10^4 cfu/mL.
A challenge model also promises an unprecedented opportunity to use modern techniques to describe the immunobiology of GAS infection. Blood and saliva samples will be collected at multiple timepoints before, during, and after the challenge. Testing of serial samples will add a dynamic next level to the clinical foundations of the challenge model, enabling in-depth comparison between participants developing pharyngitis or not and paving the way to identifying immune correlates of protection.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||50 participants|
|Intervention Model:||Sequential Assignment|
|Intervention Model Description:||Observational, sequential, dose-escalation|
|Masking:||None (Open Label)|
|Primary Purpose:||Basic Science|
|Official Title:||Group A Streptococcal Human Challenge Study: Building a Pharyngitis Model to Accelerate Vaccine Development|
|Actual Study Start Date :||June 27, 2018|
|Estimated Primary Completion Date :||October 2019|
|Estimated Study Completion Date :||April 2020|
Experimental: GAS oropharyngeal challenge
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)
Direct oropharyngeal application by swab following immersion in a solution containing a specified concentration (dose) of GAS M75.
- Proportion of participants at each GAS M75 dose level meeting the study pharyngitis endpoint [ Time Frame: Up to 6 days after challenge dose administered. ]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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03361163
|Contact: Janet Wong, MBBS,BScfirstname.lastname@example.org|
|Contact: Joshua Osowicki, MBBSemail@example.com|
|Centre for Clinical Studies (Nucleus Network Limited)||Recruiting|
|Melbourne, Victoria, Australia, 3004|
|Contact: Janet Wong, MBBS, BSc +61385939804 firstname.lastname@example.org|
|Principal Investigator: Janet Wong, MBBS, BSc|
|Principal Investigator:||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|