Peptide-based supramolecular vaccine systems

Abstract

Currently approved replication-competent and inactivated vaccines are limited by excessive reactogenicity and poor safety profiles, while subunit vaccines are often insufficiently immunogenic without co-administering exogenous adjuvants. Self-assembling peptide-, peptidomimetic-, and protein-based biomaterials offer a means to overcome these challenges through their inherent modularity, multivalency, and biocompatibility. As these scaffolds are biologically derived and present antigenic arrays reminiscent of natural viruses, they are prone to immune recognition and are uniquely capable of functioning as self-adjuvanting vaccine delivery vehicles that improve humoral and cellular responses. Beyond this intrinsic immunological advantage, the wide range of available amino acids allows for facile de novo design or straightforward modifications to existing sequences. This has permitted the development of vaccines and immunotherapies tailored to specific disease models, as well as generalizable platforms that have been successfully applied to prevent or treat numerous infectious and non-infectious diseases. In this review, we briefly introduce the immune system, discuss the structural determinants of coiled coils, β-sheets, peptide amphiphiles, and protein subunit nanoparticles, and highlight the utility of these materials using notable examples of their innate and adaptive immunomodulatory capacity. STATEMENT OF SIGNIFICANCE: Subunit vaccines have recently gained considerable attention due to their favorable safety profiles relative to traditional whole-cell vaccines; however, their reduced efficacy requires co-administration of reactogenic adjuvants to boost immune responses. This has led to collaborative efforts between engineers and immunologists to develop nanomaterial-based vaccination platforms that can elicit protection without deleterious side effects. Self-assembling peptidic biomaterials are a particularly attractive approach to this problem, as their structure and function can be controlled through primary sequence design and their capacity for multivalent presentation of antigens grants them intrinsic self-adjuvanticity. This review introduces the various architectures adopted by self-assembling peptides and discusses their application as modulators of innate and adaptive immunity.

Keywords: Immunology; Nanomaterials; Peptides; Self-assembly; Vaccines.

Fig. 1.

Supramolecular peptide, peptide amphiphile, and protein subunit nanoparticle structures. (A,B) Coiled coils are oligomers composed of two or more α-helices that typically display an abcdefg heptad repeat [33]. (C) Coil29 self-assembles into filamentous nanotubes in which individual coiled coil peptides associate with their N-termini facing radially outward (adapted with permission from [34], copyright 2017 American Chemical Society). β-sheets adopt either (D) parallel or (E) antiparallel orientation, both of which are stabilized by extensive hydrogen bonding networks [35]. β-sheets with alternating hydrophilic and hydrophobic residues are (F) facially amphipathic and (G) laminate into bilayers that (H) propagate along the hydrogen bonding axis (adapted with permission from [36], copyright 2017 American Chemical Society). (I) Peptide amphiphiles contain peptide head groups and lipid tails that assemble into cylindrical or spherical micelles (reprinted with permission from AAAS [37]). (J) Protein subunit nanoparticles incorporating trimeric and pentameric coiled coils assembly into polyhedral nanoparticles (adapted from [27], copyright 2006, with permission from Elsevier). (K) Coiled coil homotrimers covalently linked to the components of a heterodimeric coiled coil through disulfide bridges interact to form a hexagonal lattice that gives rise to closed nanocages (adapted with permission from [38], copyright 2018 American Chemical Society).

Fig. 2.

Evolution of immune responses following supramolecular peptide-based vaccine delivery. After vaccine administration (1), tissue resident APCs such as DCs and MΦs internalize the constructs and process them through either the exogenous or endogenous pathway to present the antigenic epitopes on MHC II or MHC I molecules, respectively (2). The antigen-laden APCs then migrate to the dLNs for antigen presentation to CD4⁺ or CD8⁺ T cells. The interaction between MHC molecules and TCRs is supported by costimulatory signals, including ligand–receptor interactions and cytokine signaling, which enhance T cell responses and drive differentiation (3). T_H cells then direct further immune activation through cytokine signaling and interaction with B cells and CD8⁺ T cells. Activated B cells interact with antigen-specific T cells and differentiate into plasma cells that produce long-lived antibody responses. Crosstalk between CD4⁺ and CD8⁺ T cells leads to the production of cytotoxic T lymphocytes that detect and eliminate infected cells (4). Created with https://www.BioRender.com.