Advances in the design and delivery of peptide subunit vaccines with a focus on toll-like receptor agonists

Abstract

Considerable success has been made with many peptide antigen formulations, and peptide-based vaccines are emerging as the next generation of prophylactic and remedial immunotherapy. However, finding an optimal platform balancing all of the requirements for an effective, specific and safe immune response remains a major challenge for many infectious and chronic diseases. This review outlines how peptide immunogenicity is influenced by the way in which peptides are presented to the immune system, underscoring the need for multifunctional delivery systems that couple antigen and adjuvant into a single construct. Particular attention is given to the ability of Toll-like receptor agonists to act as adjuvants. A survey of recent approaches to developing peptide antigen delivery systems is given, many of which incorporate Toll-like receptor agonists into the design.

Figure 1. Toll-like receptor signaling pathways

The TLR proteins initiate complex intracellular signaling pathways, resulting in the production of various cytokines that dictate specific immune responses. Typical ligands for the TLR domains are shown. See text for relevant references. AP1: Activator protein 1; IFN: Interferon; IKK: IκBα kinase complex; IRAK: IL-1 receptor-associated kinase; IRF: Interferon regulatory factor; MAL/TIRAP: MyD88 adapter-like TIR domain-containing adapter protein; MAPK: Mitogen-activated protein kinase; MKK: Mitogen-activated protein kinase kinase; MyD88: Myeloid differentiation primary-response gene 88; NAP: NF-κB-activating kinase-associated protein; NEMO: NF-κB essential modulator; ODN: Oligodinucleotide; SAPK/JNK: stress-activated protein kinase/c-Jun NH₂-terminal kinase; TAK: Transforming growth factor-β-activated kinase; TBK: TANK-binding kinase; TIR: Toll/IL-1 receptor; TLR: Toll-like receptor; TRAF: TNF receptor-associated factor; TRAM: TRIF-related adapter molecule; TRIF: TIR-domain-containing adapter inducing IFN-β.

Figure 2. Possible peptide antigen delivery systems

Peptide antigen–adjuvant conjugates such as (A) lipid–core peptides; (B) peptide amphiphiles self-assembled into mixed micelles (protein analogous micelles; lipid-based carriers including (C) synthetic, multifunctional vesicles and (D) endogenous exosomes containing peptide-loaded MHC molecules; (E) noninfectious virus-like particles displaying recombinant peptide antigens; (F) microparticles and nanoparticles made from many types of polymers with encapsulated or surface-conjugated peptides; and (G) solid-core nanobeads with conjugated peptides. MPLA: Monophosphoryl lipid A; ODN: Oligodinucleotide; Pam₃Cys: Tripalmitoyl-S-glyceryl cysteine; TLR: Toll-like receptor.