Human Innate Immune Responses To Mycobacterial Aerodigestive Tract Infection
Condition: Bacterial Infections
MeSH terms: Infections; Communicable Diseases; Bacterial Infections
Study type: Interventional

Summary: 
      The approach we will use is to employ measurement of the activation of white blood cells, to
      look at patterns of responses during a controlled infection of the gut with Mycobacterium
      bovis. M. bovis can be conveniently obtained in a safe and pure form as an oral vaccine. By
      giving three challenges of M bovis to the gut, we will simulate repeated gut infections with
      this organism. We can then compare the activation of cells in the blood to the immune
      responses seen after each challenge, to determine whether the non-specific defences of the
      gut can block each subsequent infection.
    

Detailed description: 
      The approach we will use is to employ immune readouts and genomics to look at patterns of
      responses during a controlled infectious challenge of the human gut.

      Genomics uses 'Affymetrix' gene arrays, and other techniques to determine the profile of gene
      expression. When a gene is 'switched on' it makes mRNA that the body uses as a template to
      make proteins. We will extract all the mRNA from white blood cells before, during and after
      an infection. The gene chips have hundreds or thousands of mini-sensors that can measure how
      much mRNA from any particular gene is present in the sample. Thus we can begin to see which
      genes are switch on or off, or unaffected, inside white blood cells during the stages of a
      developing innate immune response. This allows us to monitor the body's response to an
      infection and to see which families of genes are important at the different stages of gut
      infection.

      The BCG vaccine is derived from Mycobacterium bovis (the full name of the organism is
      Mycobacterium bovis Baccille Calmette Guérin). In this study we propose to use an oral BCG
      preparation, produced as a prophylactic and therapeutic oral vaccine, as a safe model for
      natural gut infection with pathogenic Mycobacterium bovis. The cell wall of mycobacteria such
      as BCG is a powerful immune adjuvant (an adjuvant is a substance that enhances an immune
      response) as the lipids, sugars and proteins in the cell wall interact strongly with the
      molecules of the innate immune system. It therefore provides a safe but highly effective way
      to stimulate innate immunity under 'natural' conditions of gut infection. This first model
      has been selected as it reflects a 'real world' high priority area of disease prevention,
      while having a high level of safety and reproducibility in the oral BCG model.

      By carefully delivering oral BCG challenges to healthy volunteers under controlled
      conditions, we can reduce the noise and background activity in the proteomic and genomic
      assays we will use to profile the developing innate immune response. We can check that the
      BCG has indeed colonised and 'infected' the subject by measuring the specific adaptive T cell
      and antibody responses using sensitive assays we have developed in previous studies to detect
      these immune responses. This is a critical aspect of the study: if we detect the BCG-specific
      T cell responses we can be assured that the 'infection' has taken place, and so can interpret
      the profiles we see in the immunology and genomics.

      If we see an immune response we can relate any innate immune activation to colonisation with
      BCG. In contrast, even if we see no immune responses, but can be sure that the vaccine was
      delivered properly in a viable formulation (which we will do by adhering to strict Good
      Clinical Practice) then we can look at features in the genomic and proteomic profiles in the
      baseline measurements before infection that may predict the failure of the organisms to
      infect.

      By collecting data of other events such as intercurrent illnesses, or other adverse events we
      can also determine whether changes in the proteomic or gene expression profiles are indeed
      due to the model infection, or extraneous events. This preliminary study will enable us to
      refine expensive techniques, protocols and assays to let us focus in more detail in
      subsequent studies

      This study will be conducted according to the Standard Operating Procedures (SOPs) of the St
      George's Vaccine Institute. Up to 10 subjects will be included in this study. The study will
      consist of a pre-study screening visit and 23 visits over a period of 12 month at the times
      indicated in the schedule for investigation.
    

Intervention name(s): Gut infection challenge with M bovis
Intervention type(s): Biological
Intervention description(s): Oral delivery of 100mg viable M bovis (approximately 10,000,000 viable bacilli) in 5mL 1.5% sodium glutamate solution on three occasions on days 0, 28 and 49
Other intervention name(s): Bacille Calmette Guerin "Moreau Rio de Janeiro"
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: innate immunity; mycobacterium bovis; mucosal immunity; adaptive immunity; genomics