Particulate formulations for the delivery of poly(I:C) as vaccine adjuvant ☆ Annina M. Hafner a , Blaise Corthésy b , Hans P. Merkle a, ⁎ a ETH Zurich, Institute of Pharmaceutical Sciences, CH-8093 Zurich, Switzerland b CHUV, Division of Immunology and Allergy, CH-1005 Lausanne, Switzerland abstract article info Article history: Accepted 31 May 2013 Available online xxxx Keywords: Immunostimulation TLR3 ligands Vaccine formulations Microspheres Surface modification Dendritic cells Non-professional phagocytes Efficacy Safety Autoimmunity 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 formula- tions. 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 inter- action with non-professional phagocytes and to modulate the resulting cytokine secretion profile. © 2013 Elsevier B.V. All rights reserved. Contents 1. Introduction and background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 2. Dendritic cells as a privileged target for vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 2.1. Sentinel function of DCs — Bridging innate and adaptive immunity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 3. TLR3 ligands as adjuvants in vaccination against intracellular pathogens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 3.1. Receptor expression patterns and implications on vaccination strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 3.2. Signaling induced by dsRNA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 3.3. Choosing a synthetic TLR3 ligand for adjuvant applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 3.4. Poly(I:C): A strong antiviral immunostimulant on the one hand … . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 3.5. … but implications for overstimulation and autoimmunity on the other hand . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 Advanced Drug Delivery Reviews xxx (2013) xxx–xxx Abbreviations: AIM 2, absent-in-melanoma 2; APC, antigen-presenting cell; BMDC, bone marrow-derived DC; CLR, C-type lectin receptor; CTAB, cetytrimethylammonium bromide; CTL, cytotoxic T lymphocyte; DAI, DNA-dependent activator of IFN-regulatory factor; DAMP, danger-associated molecular pattern; DC, dendritic cell; DDA, dimethyldioctadecylammonium; DEAE, diethylaminoethyl; ds, double-stranded; GM-CSF, granulocyte macrophage colony-stimulating factor; HFF, human foreskin fibroblast; iDCs, immature DCs; IFN, interferon; IL, interleukin; IP 10, IFN-γ-inducible protein 10 (CXCL10); IRF 3, IFN-regulatory factor 3; LCs, Langerhans cells; LPS, lipopolysaccharide; MDA-5, melanoma differentiation-associated gene—5; mDC, mature DC; MHC, major histocompatibility complex; mincle, macrophage-inducible C type lectin; MoDC, monocyte-derived dendritic cell; M720, Montanide ISA 720; NAP 1, neutrophil activating peptide 1; NLR, NOD-like receptor; ODN, oligodeoxynucleotide; OVA, ovalbumin; PAMP, pathogen-associated molecular pattern; pDC, plasmacytoid dendritic cell; PEI, polyethyleneimine; PK3, pH-sensitive polyketal copolymer; PLGA, poly(lactic-co-glycolic acid); PLL, poly(L-lysine); PLL-g-PEG, Poly(L-lysine)-graft-poly(ethylene glycol); PEG, poly(ethylene glycol); poly(A:U), polyriboadenylic–polyribouridylic acid; poly(IC·LC), poly(I:C) stabilized with poly(L-lysine) and carboxymethylcellulose; poly(I:C12U), Ampligen; poly(I:C), polyriboinosinic acid–polyribocytidylic acid; PRR, pathogen recognition receptor; PS, polystyrene; RIG I, retinoic acid-inducible gene-I; RLRs, retinoic acid-inducible gene-I-like receptors; SLN, solid-lipid nanoparticle; TCR, T cell receptor; TDB, trehalose 6,6′-dibehenate; TLR, Toll-like receptor; TNF-α, tumor necrosis factor-alpha. ☆ This review is part of the Advanced Drug Delivery Reviews theme issue on "Editor's Choice 2013". ⁎ Corresponding author at: ETH Zurich, Institute of Pharmaceutical Sciences, HCI H 439, Wolfgang-Pauli-Strasse 10, CH-8093 Zurich, Switzerland. Tel.: +41 44 341 56 87. E-mail address: hmerkle@pharma.ethz.ch (H.P. Merkle). ADR-12475; No of Pages 14 0169-409X/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.addr.2013.05.013 Contents lists available at SciVerse ScienceDirect Advanced Drug Delivery Reviews journal homepage: www.elsevier.com/locate/addr Please cite this article as: A.M. Hafner, et al., Particulate formulations for the delivery of poly(I:C) as vaccine adjuvant, Adv. Drug Deliv. Rev. (2013), http://dx.doi.org/10.1016/j.addr.2013.05.013