Human Innate Immune Responses To Mycobacterial Aerodigestive Tract Infection (UBC-INNATE01)
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|ClinicalTrials.gov Identifier: NCT01074775|
Recruitment Status : Completed
First Posted : February 24, 2010
Last Update Posted : February 24, 2010
|Condition or disease||Intervention/treatment||Phase|
|Bacterial Infections||Biological: Gut infection challenge with M bovis||Not Applicable|
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.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||7 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Primary Purpose:||Basic Science|
|Official Title:||An Investigation Of In Vivo Human Innate Immune Responses To Mycobacterial Aerodigestive Tract Infection|
|Study Start Date :||September 2006|
|Actual Primary Completion Date :||September 2007|
|Actual Study Completion Date :||September 2007|
Experimental: Challenge group
Recipients of three challenge infections with oral M bovis
Biological: Gut infection challenge with M bovis
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 Name: Bacille Calmette Guerin "Moreau Rio de Janeiro"
- Genomics profile [ Time Frame: 12 months (23 visits) ]Peripheral blood mononuclear cell gene expression measured by analysis of extracted mRNA using polymerase chain reaction
- Cell mediated immune responses [ Time Frame: 12 months (8 visits) ]Frequency of mycobacterium antigen-specific Interferon gamma producing cells measured in vitro by ELISpot and ELISA
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): NCT01074775
|St George's Vaccine Institute, St George's University of London|
|London, England, United Kingdom, SW17 0RE|
|Principal Investigator:||David JM Lewis, MD||St George's - University of London, UK|