Differential Sensitivity to Interepitope Spacing in Mast Cells and B Cells Enables Design of Hypoallergenic Allergen Vaccine Immunogens

Therapeutic allergen vaccine immunogens can trigger IgE-mediated mast cell activation, resulting in allergic reactions. Here, we report on a mode of hypoallergenic immunogen design that enables immunization against IgE-reactive peptide B cell epitopes by optimizing the distance between epitopes. Using DNA-based model immunogens, we show that mast cells and B cells exhibit idiosyncratic sensitivity to interepitope spacing, with mast cell activation being dampened by high interepitope spacing while B cells remain responsive to identical immunogen configurations. To exploit this finding, we construct hypoallergenic immunogens based on supramolecular peptide nanofibers with ultralow epitope density that, when used as an allergen vaccine, raise protective allergen-neutralizing IgG antibody responses. This study provides a proof-of-concept for a mode of hypoallergenic immunogen design based on nanoscale control of the distances between IgE-reactive epitopes, which may enable allergen vaccination against IgE-reactive epitope targets in the absence of allergic reactogenicity.