Controlled Human Infection for Vaccination Against Streptococcus Pyogenes
Condition: 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
MeSH terms: Infections; Communicable Diseases; Bacterial Infections; Pharyngitis; Streptococcal Infections; Gram-Positive Bacterial Infections; Hemolysis
Study type: Interventional
Phase: Phase 1

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.
    

Detailed description: 
      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.
    

Intervention name(s): emm75 Streptococcus pyogenes (GAS M75, strain 611024)
Intervention type(s): Biological
Intervention description(s): Direct oropharyngeal application by swab following immersion in a solution containing a specified concentration (dose) of GAS M75.
Other intervention name(s): GAS M75; Group A Streptococcus challenge inoculum
Intervention MeSH terms: Bromoacetylalprenololmenthane
Intervention model: Sequential Assignment
Intervention model description: Observational, sequential, dose-escalation
Masking: None (Open Label)
Primary purpose: Basic Science
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