Nanoparticle Vaccines Adopting Virus-like Features for Enhanced Immune Potentiation

Chattopadhyay, Saborni; Chen, Jui-Yi; Chen, Hui-Wen; Hu, Che-Ming Jack

In addition to delivering antigens for more effective immune processing, nanoparticles have been extensively applied to localize immunological adjuvants to lymph nodes for improved safety and potency. While conventional adjuvants such as alum have been widely employed clinically to promote humoral responses [156] , more recent development in adjuvant research has identified many pathogen-associated molecular patterns (PAMPs) as promising adjuvant candidates towards promoting both humoral and cellular responses [157] . These molecular danger signals are often similar to viral pathogens regarding their immune potentiating mechanisms, triggering innate immunity and in turn facilitating adaptive immune responses. Many PAMPs (i.e. CpG-ODN, Poly(I:C), and cyclic dinucleotides) as well as other molecular agonists of toll-like receptors (TLRs) (i.e. imiquimod and resiquimod) are known to induce strong immune responses. However, their potency poses safety concerns over the likely induction of systemic inflammation. Nanoparticle-based delivery thus offers a desirable strategy in guiding these immunological modulators to lymph nodes, increasing their effective concentration and reducing their systemic reactogenicity. In one example, Nunh et al., constructed a pH-degradable nanogel platform ligated with imidazoquinoline (IMDQ), a TLR7/8 agonist, and showed retention of the adjuvant at the injection site and the draining lymph node. The adjuvant in its free form elicited systemic inflammatory responses, but this side effect was largely obviated with the nanogel formulation. The targeting effect of the nanoformulations also resulted in recruitment of monocytes to the draining lymph node. A large number of immune cells, including B cells, DCs, and macrophages were shown to readily take up these adjuvant-loaded nanogels [158] . In another study by Ilyinskii et. al., synthetic vaccine particles encapsulating resiquimod (R848, a TLR7/8 and TLR9 ligand) augmented humoral and cellular immune responses to both soluble and nanoparticle-delivered proteins compared to that observed with free adjuvants. The adjuvant-loaded nanoparticles promoted local cytokine induction in the lymph nodes and reduced systemic cytokine production observed with free R848. Moreover, while injection of the nanoformulation led to sustained expressions of IFN-γ, IL-12, and IL-1β in lymph nodes after 48 hours, free R848 induced only modest levels of IL-12 and IFN-β [159] . CpG-ODN, an agonist of TLR-9, is another adjuvant that's frequently coupled with nanocarriers for vaccination studies [11, 67, 100, 101, 160, 161] . Some of the primary advantages of nanoparticle-based CpG formulations include strong T cell responses, dosage sparing, and reduced systemic side effects. Such formulations have been commonly applied in anticancer vaccination efforts owing to the need for high cell-based immune responses for effective tumor containment.