Supramolecular peptide immunotherapies for peanut allergy

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Peanut allergy is the leading cause of allergy-related deaths in children and is primarily managed through strict allergen avoidance, which increases anxiety and lowers quality of life. Among current clinical or investigational treatments, peanut oral immunotherapy (OIT) and sublingual immunotherapy (SLIT) have shown efficacy, but both strategies require a lifetime of daily management, impacting patient compliance and cost. Further, SLIT regimens have exhibited comparably better safety profiles than OIT in clinical trials, but they are less effective at inducing allergen desensitization. Conversely, OIT has exhibited greater efficacy but carries a greater risk of adverse effects, including anaphylaxis. The therapeutic efficacy of both OIT and SLIT is associated with a shift in T-cell phenotype from Th2 to Th1 and a shift in antibody isotype from IgE to IgG and IgA, although the relative contributions of these immunological changes have not been fully elucidated. Ideally, the sublingual administration of carefully chosen peptide B-cell epitopes from allergens could improve the safety profile of allergy immunotherapies, but raising antibody responses against peptide epitopes sublingually has proven a significant challenge. This project seeks to exploit a recently designed platform for sublingual immunization based on supramolecular peptide-polymer nanomaterials, which have been shown very recently to raise strong IgG responses when delivered sublingually either in tablet form or in liquid formulations. These materials will be designed such that rationally selected linear B-cell epitopes and sublingual delivery combine to produce a novel therapy capable of raising protective antibody responses against selected epitopes in peanut antigens, while minimizing risks of anaphylaxis. After selecting linear B cell epitopes from major peanut allergens maximizing sublingual immunogenicity and minimizing reactogenicity in vitro, multi-epitope nanomaterial vaccines will be investigated in a mouse model of allergen desensitization and peanut challenge. The project capitalizes on a multi-disciplinary collaboration between research groups with expertise in immune engineering and biomaterials (research group of Joel Collier in the Department of Biomedical Engineering) and allergy, vaccination, and adjuvants (research group of Herman Staats in the Department of Pathology). At the conclusion of this two-year high risk/high reward R21 project, we expect to have demonstrated a critical proof-of- concept establishing supramolecular sublingual peptide nanomaterials as a potential immunotherapy for peanut allergy desensitization that can be comprehensively investigated in follow-on work.