Bacterial Infections Clinical Trial
Official title:
An Investigation Of In Vivo Human Innate Immune Responses To Mycobacterial Aerodigestive Tract Infection
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.
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.
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Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Basic Science
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