Current research and development of antigens for vaccination often center on purified recombinant proteins, viral subunits, synthetic oligopeptides or oligosaccharides, most of them suffering from being poorly immunogenic and subject to degradation. Hence, they call for efficient delivery systems and potent immunostimulants, jointly denoted as adjuvants. Particulate delivery systems like emulsions, liposomes, nanoparticles and microspheres may provide protection from degradation and facilitate the co-formulation of both the antigen and the immunostimulant. Synthetic double-stranded (ds) RNA, such as polyriboinosinic acid-polyribocytidylic acid, poly(I:C), is a mimic of viral dsRNA and, as such, a promising immunostimulant candidate for vaccines directed against intracellular pathogens. Poly(I:C) signaling is primarily dependent on Toll-like receptor 3 (TLR3), and on melanoma differentiation-associated gene-5 (MDA-5), and strongly drives cell-mediated immunity and a potent type I interferon response. However, stability and toxicity issues so far prevented the clinical application of dsRNAs as they undergo rapid enzymatic degradation and bear the potential to trigger undue immune stimulation as well as autoimmune disorders. This review addresses these concerns and suggests strategies to improve the safety and efficacy of immunostimulatory dsRNA formulations. The focus is on technological means required to lower the necessary dosage of poly(I:C), to target surface-modified microspheres passively or actively to antigen-presenting cells (APCs), to control their interaction with non-professional phagocytes and to modulate the resulting cytokine secretion profile.
Keywords: AIM 2; APC; Ampligen; Autoimmunity; BMDC; C-type lectin receptor; CLR; CTAB; CTL; DAI; DAMP; DC; DDA; DEAE; DNA-dependent activator of IFN-regulatory factor; Dendritic cells; Efficacy; GM-CSF; HFF; IFN; IFN-regulatory factor 3; IFN-γ-inducible protein 10 (CXCL10); IL; IP 10; IRF 3; Immunostimulation; LCs; LPS; Langerhans cells; M720; MDA-5; MHC; Microspheres; MoDC; Montanide ISA 720; NAP 1; NLR; NOD-like receptor; Non-professional phagocytes; ODN; OVA; PAMP; PEG; PEI; PK3; PLGA; PLL; PLL-g-PEG; PRR; PS; Poly(l-lysine)-graft-poly(ethylene glycol); RIG I; RLRs; SLN; Safety; Surface modification; T cell receptor; TCR; TDB; TLR; TLR3 ligands; TNF-α; Toll-like receptor; Vaccine formulations; absent-in-melanoma 2; antigen-presenting cell; bone marrow-derived DC; cetytrimethylammonium bromide; cytotoxic T lymphocyte; danger-associated molecular pattern; dendritic cell; diethylaminoethyl; dimethyldioctadecylammonium; double-stranded; ds; granulocyte macrophage colony-stimulating factor; human foreskin fibroblast; iDCs; immature DCs; interferon; interleukin; lipopolysaccharide; mDC; macrophage-inducible C type lectin; major histocompatibility complex; mature DC; melanoma differentiation-associated gene—5; mincle; monocyte-derived dendritic cell; neutrophil activating peptide 1; oligodeoxynucleotide; ovalbumin; pDC; pH-sensitive polyketal copolymer; pathogen recognition receptor; pathogen-associated molecular pattern; plasmacytoid dendritic cell; poly(A:U); poly(I:C); poly(I:C) stabilized with poly(l-lysine) and carboxymethylcellulose; poly(I:C12U); poly(IC·LC); poly(ethylene glycol); poly(l-lysine); poly(lactic-co-glycolic acid); polyethyleneimine; polyriboadenylic–polyribouridylic acid; polyriboinosinic acid–polyribocytidylic acid; polystyrene; retinoic acid-inducible gene-I; retinoic acid-inducible gene-I-like receptors; solid-lipid nanoparticle; trehalose 6,6′-dibehenate; tumor necrosis factor-alpha.
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