Particulate formulations for the delivery of poly(I:C) as vaccine adjuvant

• Published in: Advanced drug delivery reviews Vol. 65; no. 10; pp. 1386 - 1399
• Main Authors: Hafner, Annina M., Corthésy, Blaise, Merkle, Hans P.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.10.2013
• Subjects: Adjuvants, Immunologic - administration & dosage; Adjuvants, Immunologic - chemistry; Animals; Antigens - administration & dosage; Antigens - chemistry; Autoimmunity; Dendritic cells; Dendritic Cells - immunology; Efficacy; Humans; Immunostimulation; Microspheres; Non-professional phagocytes; Poly I-C - administration & dosage; Poly I-C - chemistry; Safety; Surface modification; TLR3 ligands; Toll-Like Receptor 3 - immunology; Vaccine formulations; Vaccines - administration & dosage; Vaccines - chemistry; Autoimmunity; PS; poly(I:C12U); CLR; Non-professional phagocytes; HFF; MHC; ds; IP 10; PRR; Microspheres; SLN; BMDC; GM-CSF; Vaccine formulations; ODN; PK3; IL; Immunostimulation; NAP 1; poly(A:U); mDC; poly(IC·LC); IRF 3; OVA; RIG I; RLRs; DDA; AIM 2; TCR; CTAB; LPS; IFN; PLL; TDB; NLR; TLR; TLR3 ligands; Safety; LCs; Surface modification; Dendritic cells; MoDC; Efficacy; M720; DAI; MDA-5; pDC; PLL-g-PEG; mincle; PAMP; PLGA; PEG; APC; TNF-α; PEI; poly(I:C); CTL; DEAE; iDCs; DAMP; DC; neutrophil activating peptide 1; Montanide ISA 720; trehalose 6,6′-dibehenate; major histocompatibility complex; pH-sensitive polyketal copolymer; tumor necrosis factor-alpha; cetytrimethylammonium bromide; Toll-like receptor; bone marrow-derived DC; T cell receptor; solid-lipid nanoparticle; dimethyldioctadecylammonium; Langerhans cells; immature DCs; lipopolysaccharide; dendritic cell; polyriboinosinic acid–polyribocytidylic acid; polyriboadenylic–polyribouridylic acid; retinoic acid-inducible gene-I; plasmacytoid dendritic cell; monocyte-derived dendritic cell; polystyrene; double-stranded; diethylaminoethyl; mature DC; poly(lactic-co-glycolic acid); poly(I:C) stabilized with poly(l-lysine) and carboxymethylcellulose; melanoma differentiation-associated gene—5; poly(ethylene glycol); ovalbumin; C-type lectin receptor; oligodeoxynucleotide; granulocyte macrophage colony-stimulating factor; IFN-γ-inducible protein 10 (CXCL10); absent-in-melanoma 2; cytotoxic T lymphocyte; human foreskin fibroblast; Poly(l-lysine)-graft-poly(ethylene glycol); polyethyleneimine; pathogen recognition receptor; DNA-dependent activator of IFN-regulatory factor; antigen-presenting cell; interleukin; pathogen-associated molecular pattern; NOD-like receptor; poly(l-lysine); IFN-regulatory factor 3; interferon; danger-associated molecular pattern; retinoic acid-inducible gene-I-like receptors; Ampligen; macrophage-inducible C type lectin
• ISSN: 0169-409X; 1872-8294; 1872-8294
• DOI: 10.1016/j.addr.2013.05.013

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. [Display omitted]