Pathogen-associated molecular patterns on biomaterials: a paradigm for engineering new vaccines

Abstract

Vaccine development has progressed significantly and has moved from whole microorganisms to subunit vaccines that contain only their antigenic proteins. Subunit vaccines are often less immunogenic than whole pathogens; therefore, adjuvants must amplify the immune response, ideally establishing both innate and adaptive immunity. Incorporation of antigens into biomaterials, such as liposomes and polymers, can achieve a desired vaccine response. The physical properties of these platforms can be easily manipulated, thus allowing for controlled delivery of immunostimulatory factors and presentation of pathogen-associated molecular patterns (PAMPs) that are targeted to specific immune cells. Targeting antigen to immune cells via PAMP-modified biomaterials is a new strategy to control the subsequent development of immunity and, in turn, effective vaccination. Here, we review the recent advances in both immunology and biomaterial engineering that have brought particulate-based vaccines to reality.

Figure 1.

Particles with ligands that target TLRs, NLRs, or CLRs. (a) Signaling. Nano- or microparticles encapsulate antigenic components or incorporate agonists for surface or endosomal TLRs, intracellular NLRs, or membrane-bound CLRs. Particle components promote the production of proinflammatory cytokines and often the expression of co-stimulatory molecules and MHC complexes, thus leading to increased vaccine efficacy. (b) Antigen presentation. Once endocytosed, particles might be degraded in the endosome and access the MHC class II pathway, thereby activating CD4⁺ T cells (Pathway A). Alternatively, particles might escape the endosome so that encapsulated antigen can be processed in the cytosolic space and be presented via MHC class I to CD8⁺ T cells (Pathway B).

Figure 2.

Schematic diagram showing a variety of possible chemistries for conjugation of PAMP moieties to functionalized substrates. (a,b) Covalent coupling of an amine (-NH₂)-functionalized surface or PAMP to a carboxylate (-COOH) functional group, as mediated by NHS/carbodiimide reactive intermediate chemistry. (c) Carbohydrate PAMPs with unreactive hydroxylate groups might be oxidized with an agent such as sodium periodate, which yields a reactive aldehyde that can be conjugated to a dihydrazide-modified surface. The resultant hydrazone linkage is very stable. (d,e) Thiol-modified PAMPs might be linked to a maleimide-functionalized surface through selective reaction or a thiol-modified surface. (f) Histidine-tagged molecules can selectively bind to Ni chelated by tetradentate nitrilotriacetic acid: a procedure widely used for affinity separations. (g) An example of click chemistry; an azide (N₃)–alkyne cycloaddition catalyzed by a Cu(I) catalyst results in the formation of a stable triazole linkage at room temperature.