Engineering Hypoallergenic Allergen Vaccine Immunogens Based on Self-Assembling Supramolecular Peptide Nanofibers

Abstract

Allergen immunotherapies are often successful at desensitizing allergic patients but require frequent dosing and suffer from adverse events including instances of systemic anaphylaxis, leading to poor patient compliance and high cost. Allergen vaccines, in turn, can generate more durable immunological allergen desensitization with far fewer doses. However, like immunotherapies, allergen vaccines are often highly reactogenic in allergic patients – hampering their use in therapeutic settings. Much work has been dedicated to the design of “hypoallergenic” immunogens that do not elicit allergic reactions when administered to allergic patients. Typically, these strategies involve the removal, disruption, or masking of IgE-reactive B cell epitopes from the allergen immunogen to avoid Type I hypersensitivity reactions. However, these epitopes are critical targets for vaccine-elicited IgG, and immunogenicity and desensitization can be negatively impacted by their omission. Here, we report on two new modes of hypoallergenic allergen vaccine immunogen design that allow for immunization specifically against IgE-reactive B cell epitopes using self-assembling peptide nanofibers as allergen vaccine immunogens.In the work detailed in Chapter 3, we utilize a peptide-based self-assembling nanofiber platform to design allergen vaccines against IgE-reactive allergen B cell epitopes that do not elicit systemic anaphylaxis when administered subcutaneously to allergic mice. We show that, in contrast to protein vaccines, nanofiber vaccines prevent leakage of allergen material into the vascular compartment – a feature that likely underpins their reduced systemic reactogenicity. Further, we show that our allergen vaccine platform elicits therapeutic IgG antibody responses capable of desensitizing allergic mice to allergen-induced Type I hypersensitivity reactions. Finally, we have demonstrated proof-of-concept for the therapeutic potential of nanofiber-based peanut allergen vaccines directed against peanut allergen-derived epitopes. In Chapter 4, 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 inter-epitope spacing, with mast cell activation being dampened by high inter-epitope spacing while B cells remain responsive to identical immunogen configurations. To exploit this finding, we construct a new class of hypoallergenic immunogens based on supramolecular peptide nanofibers with ultra-low 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 novel 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.