Evaluation of ex vivo human CD4 T cell immune response against peanut allergens for a novel therapeutic peanut allergy vaccine
Chief Investigator: Preethi Eldi (Early Career Researcher)
Funding Amount: $38,000
Recipient: University of South Australia
Food allergy affects up-to 10% of children and in the absence of licensed therapeutics, Australia recorded the highest increase in food-induced anaphylactic reactions over the last decade. We have developed an immunotherapeutic vaccine that in authentic mouse models of peanut allergy has been shown to promote allergen desensitization. In this study, we propose complimentary ex vivo studies using cells from clinically- confirmed peanut allergic individuals to confirm the capacity of the vaccine to induce a tolerant response in human samples. This evidence of human translational potential will be a principal determinant for success in future clinical trials.
Researchers: Dr Preethi Eldi, Prof John Hayball Dr William Smith
Research Completed: 2021
Research Findings: Peanut allergy is a common cause of food-induced anaphylactic reactions in Australia and is a major burden to our healthcare system. Current clinical practice advice dietary avoidance to prevent fatal anaphylactic responses. We have developed an immunomodulatory vaccine that is designed to re-write the immune response to peanut antigens, from an allergic to a tolerant phenotype. This study has established the immunogenicity of the vaccine in ex vivo culture systems demonstrating human translational capacity.
The global prevalence of food allergy, particularly peanut allergy has increased significantly over in the past decade. In Australia, approximately 3% of children between 1-14 years are allergic to peanuts, most of them remaining allergic through-out their life. Strict dietary avoidance of peanut is the only way to prevent potentially fatal anaphylactic reactions. Recently, an oral immunotherapy product, Palforzia, has been approved by FDA not as a cure, but mostly to reduce the risk of life-threatening consequences upon inadvertent ingestion.
In the quest to induce peanut specific desensitization and/or tolerance, we have developed a peanut hypoallergenic vaccine that aims to shift the immune response to peanut from allergic to tolerant by using viral vector to deliver the peanut antigens. Following vaccination, antigen presenting cells known as dendritic cells take up the vaccine, process and present parts of the vaccine to immune cells and this cross talk between the dendritic cell and the immune cells initiates an antigen-specific immune response. In this project, we aim to examine this vaccine-mediated cross talk and confirm the induction of peanut-specific tolerant responses in cell cultures that simulate the vaccination strategy. Briefly, dendritic cells from peanut-allergic and tolerant were either pulsed with peanut or the vaccine and then cultured with T cells. Two weeks after the crosstalk, the cultures were exposed to peanut and the phenotype of the T cells were examined by flow cytometry. The key outcomes from all the various culture conditions set up are as follows:
- The peanut hypoallergenic vaccine effectively upregulates markers associated with activation on the dendritic cells and releases molecules such as interferon-gamma that create a milieu for skewing key immune cells towards a tolerant phenotype.
- In cultures set up from peanut allergic samples, the cultures that were vaccinated had a Th1 profile i.e, the number of interferon-gamma producing cells were greater than the IL-4 producing cells. In comparison, un-vaccinated cultures had a Th2 profile i.e., the IL-4 producing cell numbers were greater that interferon-gamma producing cell numbers. This confirms that the vaccine is capable of inducing a peanut specific tolerant immune response.
- The culture systems were custom developed to test the vaccine and we set up repeat cultures at different times to confirm that the assay was reproducible with consistent readouts.
- The switch in Th1 / Th2 status of the culture was specific to peanut i.e., the responses were antigen specific. This was confirmed using two controls: an empty vaccine vector to control for the vaccine and the use of a different allergen as a stimulant to control for the antigen.
- The tolerant peanut-specific T cell responses could be maintained in long-term cultures.
- Using two vaccine candidates we could demonstrate that vaccine platform used was capable of providing the Th1 milieu that influences the immune cells to have a tolerant phenotype without the need of any additional factors or inserts to facilitate the switch.
Taken together, this data suggests that the peanut hypoallergenic vaccine is capable of inducing a switch in peanut specific immune responses from allergic to tolerant phenotype. We are now currently testing this in allergy models with a complete immune system to accommodate the complexities of both the disease and treatment.
Research Papers: We aim to publish the results generated from this study in combination with the allergy model data which is currently in progress. Preliminary data from this study was used to secure further funding to set up the allergy models to test both the prophylactic and therapeutic potential of the vaccine. Data from this study was presented at the Adelaide Biomed city Research series.
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