Asthma is a chronic lung disease affecting some 150 million people worldwide. An estimated 20.3 million Americans have asthma, of which 6.3 million are children. The current therapeutic approaches for the treatment of asthma, whose prevalence and mortality are increasing, have had limited impact on clinical management and resolution of the disorder. The eotaxin family of CC chemokines and the pro- inflammatory cytokines, IL-5 and IL-13, have been shown to specifically direct and orchestrate many of the characteristic features of the disease, namely airway inflammation, bronchial hyper-reactivity and airway remodeling. The study is designed to provide proof-of-concept for the development of an immunotherapeutic vaccine for the treatment of asthma and other allergic diseases. Our novel vaccination strategy of active immunization with a multi-epitope construct formulated in Mercia's proprietary adjuvant/delivery system, MAS-1, aims to induce the host's own immune system to generate endogenous antibodies to simultaneously neutralize the asthma targets eotaxins, IL-5 and IL-13. Mercia's preliminary data have shown the efficacy and safety of this proprietary vaccine approach to neutralize secreted hormones. Significantly, preliminary data obtained from clinical trials show that this strategy does not induce autoimmunity to endogenous soluble mediators, and that the antibody titers wane when booster immunizations are discontinued. Our strategy to select the optimal immunogenic constructs involves the active immunization of mice with the peptide conjugates in MAS-1 adjuvant followed by in vivo and in vitro functional assays to show that neutralizing antibodies are induced and capable of inhibiting the biological activity of the respective recombinant murine chemokines/cytokines. Selected conjugated vaccine constructs are evaluated for therapeutic potential in a mouse model of asthma. Mice are first sensitized and challenged with an allergen, then vaccinated with the immunogenic constructs in MAS-1, followed by challenge with allergen. This proof of concept study aims to test the hypothesis that therapeutic vaccination will produce neutralizing antibodies that concertedly reduce the bioactivity of eotaxins, IL-5 and IL-13 attenuating the allergen-induced asthma phenotype, namely bronchial hyper-responsiveness, airways inflammation and mucus secretion.
Public Health Relevance: Asthma constitutes a significant healthcare problem in the U.S with about one in twenty Americans, or nearly 20 million people, suffering from this chronic inflammatory disorder of the airways, estimated to cost the US $27.6 billion annually. A therapy that addresses the underlying cause of the disease and prevents disease progression would provide a significant benefit to the patient. The proposed therapeutic vaccine targeting key mediators, shown to be important in the disease, could help fulfil this need.
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