2.3 Advantages of Nanoparticles as vaccine adjuvants
2.3.1 Improving uptake of antigens:
Particulate carriers enhance the uptake of antigens by antigen-presenting cells (APCs) such as dendritic cells (DCs) or macrophages. Nam-Hyuk Cho 35 studied the effect of zinc oxide and iron oxide nanoparticles on the uptake of tumour antigens in the dendritic cells. They showed that soluble tumour antigen did not show uptake in the dendritic cells, however when the antigen was loaded into the nanoparticles, the nanoparticles enhanced the uptake of the tumour antigen.
2.3.2 Controlling the release of antigens:
Particulate carriers can enhance the immune response by modulating the release of antigens. Demento et. al. studied the effect of the release of antigen from PLGA on the T cell response. The sustained release of the antigens the slow release of antigens enhanced the immune response.36 Similar results were obtained when Inter bilayer-crosslinked multilamellar vesicles (ICMV). Inter bilayer crosslinking via divalent magnesium cation-based fusion produced stable entrapment for protein antigens within the core. OVA used as a model antigen provided the sustained release of antigens and improved the antigen-specific CD8+ T cell immune response in comparison with the uncrosslinked liposomes with faster antigen release.37
2.3.2 Co-delivery of immunostimulatory compounds
Particle-based adjuvants may possess the ability to modulate the type of immune responses induced when used alone or in combination with other immunostimulatory compounds. Nanoparticles can be linked to multiple immunostimulatory compounds (pattern recognition receptors, APC targeting antibodies) at the same time. This co-packaging of the multiple stimulations to the immune cells help in improving the efficacy of the adjuvant system. The recent study by Gause et. al conjugated NOD2 and TLR9 agonist to mesoporous silica nanoparticles. The results showed that NP with NOD and TLR9 agonist had higher immune response in mice as compared to the agonist alone.38
2.3.3 Cross presentation of antigen:
Particulate vaccines can potentially cross-present antigen, and antigen cross-presentation is especially important to generate CD8+ T-cell responses against viral infections. The antigens which are located in the cytoplasm are expressed on the cell surface as Major histocompatible complex I (MHCI). This MHC-I peptide activates a cascade reaction which causes activation of CD-8 T cells. The endocytosed material can be presented on MHC-I through cross-presentation. The cross-presentation of the antigen as described help in inducing the CD8 T cells which then leave lymphoid sites and search and kill infected cells. The CD8-T cell is particularly important in the maintenance of effective immune control against intracellular pathogens and cancer. Recently Chanyoung Song and co-authors showed that Poly Lactic-co-Glycolic Acid (PLGA) NPs coated with Polyethyleneimine (PEI) could efficiently cross-present the antigen on the surface of the antigen presenting cells.39 Similar results were obtained when pluronic stabilised PPS nanoparticles with very small dimension of 30 nm was used to deliver antigen ovalbumin (OVA) in pulmonary parenchyma. Nembrini et.al. coupled antigen OVA and CpG through disulphide link to the nanoparticles and studied the cross-presentation of antigens in the antigen presenting cells. The disulphide bond enabled the release of the antigens specifically in the endosomes enabling the cross presentation of the antigens and thus enhancement of cytotoxic T cells which further protected mice from morbidity following influenza-ova infection.40
2.3.5 Modulation of the epitope concentrations on the nanoparticles
Soluble subunit vaccine has poor immunogenicity as the B cells have developed to recognise the repetitive epitopes on the pathogens. The density of the epitopes on the antigen surface could help to modulate the immune response. Nanoparticles by itself can modulate the density of the epitopes attached to its surface. Jegerlehner et. al. synthesised Virus-like particles (VLPS) displaying various different degrees of epitope repetitiveness. They showed that 60 epitopes with 5- 10 nm spacing induced the highest humoral immune response in mice.41 Moreover, it is also observed that small antigens like haptens are difficult to be delivered by itself. Hence it needs to be delivered by covalently attaching to large proteins.