Application of built-in adjuvants for epitope-based vaccines

Abstract

Several studies have shown that epitope vaccines exhibit substantial advantages over conventional vaccines. However, epitope vaccines are associated with limited immunity, which can be overcome by conjugating antigenic epitopes with built-in adjuvants (e.g., some carrier proteins or new biomaterials) with special properties, including immunologic specificity, good biosecurity and biocompatibility, and the ability to vastly improve the immune response of epitope vaccines. When designing epitope vaccines, the following types of built-in adjuvants are typically considered: (1) pattern recognition receptor ligands (i.e., toll-like receptors); (2) virus-like particle carrier platforms; (3) bacterial toxin proteins; and (4) novel potential delivery systems (e.g., self-assembled peptide nanoparticles, lipid core peptides, and polymeric or inorganic nanoparticles). This review primarily discusses the current and prospective applications of these built-in adjuvants (i.e., biological carriers) to provide some references for the future design of epitope-based vaccines.

Keywords: Biological carriers; Built-in adjuvants; Epitope-based vaccines; Nanoparticles.

Figure 1. The basic process of immune response in vivo.

The antigen is ingested and processed by immature antigen-presenting cells (e.g., DCs), APCs becomes mature under the action of immune-stimulating molecules. Mature APCs can express antigen information on its surface in the form of antigen peptide-MHC molecular complex and present it to T cells. After recognizing this complex, T cells are activated, proliferated, and differentiated into different subtypes of effector T cells (CD4⁺ and CD8⁺) to participate in the regulation of antigen-specific humoral and cellular immune responses.

Figure 2. The signaling pathways of TLRs.

The extracellular parts of TLRs are activated after binding with ligands, and the conformation changes lead to convergence of downstream molecules, which triggers the signaling pathway and induced the up-regulation and activation of cytokines, chemokines, and other co-stimulatory factors. With the exception of TLR3, all TLRs initiate MyD88 through the expressed MyD88 or simultaneous bridging MAL, and then activate the NF-kB and MAPK through tandem reactions, which induces the production of pro-inflammatory cytokines such as IL-1, IL-6, TNF-α, etc. The overexpression of both TRIF and TRAM or TRIF alone initiated the TRIF dependent pathway, the TRIF dependent pathway activates IFN regulatory factors and mediates the production of type I IFNs. In addition, the activation of TLR4 is related to both pathways.

Figure 3. The chemical structures of different TLR2-targeting Pam lipopeptides.

(A) Pam2Cys and Pam3Cys lipopeptides. (B) MALP-2 and FSL-1 lipopeptides. (C) Pam2CSK4 and Pam3CSK4 lipopeptides.

Figure 4. Recombinant HBc-based VLPs or HBs-based VLPs.

(A) (1) The HBc proteins naturally form the dimers, the building blocks that forms the VLPs. It takes about 60 such dimers (i.e., 120 copies of HBc) to form a HBc-based VLP. The results showed that there were about 40 amino acid residues inserted into the N-terminal of HBc. In the MIR region of HBc, 50 or 100 amino acid residues can be inserted, and as many as 100 or more residues at the C-terminal do not interfere with the formation of particles. (2) Hepatitis B surface antigen (HBsAg) can also self-assemble into highly organized viroid particles with a diameter of 22 nm. These HBs-derived VLPs contain about 100 HBsAg molecules and provide a unique opportunity to display multiple exogenous epitopes. (B) Hepatitis B virus tandem core platform. The two replicas of HBc protein are linked together by covalent bonds through flexible amino acid sequences so that the fused dimers can be folded correctly and assembled into HBc particles. In the assembled HBc particles, the four helix bundles formed at each dimer interface appear on the surface as prominent “spikes”. The tip of the spike is the preferred site for inserting foreign sequences for bivalent vaccine.

Figure 5. The schematic diagram of MAP system and LCP nanoparticles.

(A) MAP epitope vaccine based on lysine scaffold. (B) The LCP nanoparticles.

Figure 6. Self-assembled peptides nanoparticles (SAPNs).

Systematic self-assembling peptides (β-sheet nanofiber vaccine) with antigen epitopes.

Figure 7. The inorganic nanoparticles.

The formation of gold nanoparticles carrying antigen epitopes.