Tuning Helical Peptide Nanofibers as a Sublingual Vaccine Platform for a Variety of Peptide Epitopes

Abstract Mucosal immune responses to vaccination are essential for achieving full protection against pathogens entering their host at mucosal sites. However, traditional parenteral immunization routes commonly fail to raise significant mucosal immunity. Sublingual immunization is a promising alternative delivery route to raise robust immune responses both systemically and at mucosal sites, and nanomaterial‐based subunit vaccine platforms offer opportunities for raising epitope‐specific responses. Here, sublingual immunization is reported using the Coil29 platform of coiled‐coil self‐assembling peptide nanofibers. The successful immunization with epitopes of varying physicochemical properties by including mucus‐modulating components – namely sequences of proline, alanine, and serine (PAS) is demonstrated. PASylation is shown to decrease mucin complexation and increase epithelial penetration in vitro, enabling sublingual immunization against a variety of selected peptide epitopes in vivo. Coil29 fibers are also readily formed into tablets for solid‐state dosing formulations and maintain their immunogenicity in this state. Previous sublingual peptide nanofiber immunotherapies have been based on different structures, such as highly stable β‐sheets. The present work demonstrates that alternatively folded structures such as α‐helical nanofibers can also be rendered sublingually immunogenic, enabling immunization with a variety of peptide epitopes and offering additional ways to specify mucus interactions, delivery state, dosing, and formulation.