Harnessing the Activation of Toll-Like Receptor 2/6 by Self-Assembled Cross-β Fibrils to Design Adjuvanted Nanovaccines

• Main Authors: Soultan Al-Halifa, Ximena Zottig, Margaryta Babych, Mélanie Côté-Cyr, Steve Bourgault, Denis Archambault
• Format: Article
• Language: English
• Published: MDPI AG 2020-10-01
• Series: Nanomaterials
• Subjects: nanovaccine; fibrils; self-assembly; immune response; immunization; toll-like receptor
• Online Access: https://www.mdpi.com/2079-4991/10/10/1981

Protein fibrils characterized with a cross-β-sheet quaternary structure have gained interest as nanomaterials in biomedicine, including in the design of subunit vaccines. Recent studies have shown that by conjugating an antigenic determinant to a self-assembling β-peptide, the resulting supramolecular assemblies act as an antigen delivery system that potentiates the epitope-specific immune response. In this study, we used a ten-mer self-assembling sequence (I₁₀) derived from an amyloidogenic peptide to biophysically and immunologically characterize a nanofibril-based vaccine against the influenza virus. The highly conserved epitope from the ectodomain of the matrix protein 2 (M2e) was elongated at the N-terminus of I₁₀ by solid phase peptide synthesis. The chimeric M2e-I₁₀ peptide readily self-assembled into unbranched, long, and twisted fibrils with a diameter between five and eight nm. These cross-β nanoassemblies were cytocompatible and activated the heterodimeric Toll-like receptor (TLR) 2/6. Upon mice subcutaneous immunization, M2e-fibrils triggered a robust anti-M2e specific immune response, which was dependent on self-assembly and did not require the use of an adjuvant. Overall, this study describes the efficacy of cross-β fibrils to activate the TLR 2/6 and to stimulate the epitope-specific immune response, supporting usage of these proteinaceous assemblies as a self-adjuvanted delivery system for antigens.