Development of a vaccine for Coeliac Disease
Coeliac disease (CD) is a lifelong immune disease caused by ingesting gluten derived from wheat, rye, barley and sometimes oats, affecting around 1% of Australian, European, American, Middle Eastern, West and South Asian populations. CD can be associated with a diverse range of clinical presentations and significant medical complications (e.g. malnutrition, osteoporosis, infertility, liver failure, cancer). A gluten free diet is the only treatment but is expensive and difficult to comply with. In patients with CD, daily consumption of 50mg of gluten, equivalent to that contained in a 1/100th of a slice of standard wheat bread, damages the small intestine.
Many of the drugs under development for coeliac disease are likely to supplement the gluten free diet and simply provide a safeguard against inadvertent gluten exposure. Long-acting agents that qualitatively change the immune response to gluten, such as peptide-based therapeutic vaccines, are likely to replace gluten free diet if they prove efficacious. In 95% of cases CD is associated with a gene encoding HLA-DQ2, with the remaining 5% associated with HLA-DQ8.. We have developed a peptide-based therapeutic vaccine for HLA-DQ2+ CD based on ‘immuno-dominant’ T-cell epitopes of gluten; regions of gluten that trigger vigorous T-cell responses in the majority of people with the disease.
Whole antigen immunotherapy provides long-term remission in allergic diseases such as hay-fever [1], while a prototype vaccine using allergen (Fel-d1)-derived peptides recognized by CD4 T cells in cat-sensitive asthma shows efficacy in Phase II clinical trials [2]. In common with traditional whole antigen immunotherapy, peptide-based therapeutic vaccines delivered in multiple small doses over a course of injections or mucosal applications can induce immune tolerance not only to the selected immuno-dominant epitopes or protein but also potentially spreading to involve other sub-dominant pathogenic epitopes.
A comprehensive pre-clinical programme has been successfully completed and we are now finalising preparations for a Phase Ib clinical trial in Melbourne in 2009.
Dr. Robert Anderson with a vial of the therapeutic peptide vaccine he and his team have developed for coeliac disease.
1. Durham SR, Walker SM, Varga EM, Jacobson MR, O'Brien F, Noble W, Till SJ, Hamid QA, Nouri-Aria KT: Long-term clinical efficacy of grass-pollen immunotherapy. N Engl J Med 1999;341:468-475.
2. Oldfield WL, Kay AB, Larche M: Allergen-derived T cell peptide-induced late asthmatic reactions precede the induction of antigen-specific hyporesponsiveness in atopic allergic asthmatic subjects. J Immunol 2001;167:1734-1739.