Inflammasome-activating nanoparticles as modular systems for optimizing vaccine efficacy

• Published in: Vaccine 2009-05, Vol.27 (23), p.3013-3021
• Main Authors: Demento, Stacey L, Eisenbarth, Stephanie C, Foellmer, Harald G, Platt, Craig, Caplan, Michael J, Mark Saltzman, W, Mellman, Ira, Ledizet, Michel, Fikrig, Erol, Flavell, Richard A, Fahmy, Tarek M
• Format: Article
• Language: English
• Subjects: Adjuvants, Immunologic - metabolism; Adjuvants, Immunologic - therapeutic use; Allergy and Immunology; Alum; Aluminum; Animals; Antibody Formation; Applied microbiology; Biological and medical sciences; Carrier Proteins - immunology; Carrier Proteins - metabolism; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Crystals; Dendritic Cells - immunology; Dendritic Cells - metabolism; Fundamental and applied biological sciences. Psychology; Immune response; Immune system; Inflammasome; Lactic Acid - immunology; Lipopolysaccharides - immunology; Medical research; Mice; Mice, Inbred C57BL; Microbiology; Miscellaneous; Nanoparticles; Nanoparticles - therapeutic use; Nanotechnology; NLR Family, Pyrin Domain-Containing 3 Protein; Pattern recognition; PLGA; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Silica; Vaccination - methods; Vaccines; Vaccines, antisera, therapeutical immunoglobulins and monoclonal antibodies (general aspects); Viral Envelope Proteins - immunology; Virology; West Nile Fever - immunology; West Nile Fever - metabolism; West Nile Fever - prevention & control; West Nile virus; West Nile Virus Vaccines - immunology; West Nile Virus Vaccines - therapeutic use
• ISSN: 0264-410X; 1873-2518
• DOI: 10.1016/j.vaccine.2009.03.034

Abstract Innate immune system activation is a critical step in the initiation of an effective adaptive immune response; therefore, activation of a class of innate pathogen receptors called pattern recognition receptors (PRR) is a central feature of many adjuvant systems. It has recently been shown that one member of an intracellular PRR, the NLRP3 inflammasome, is activated by a number of classical adjuvants including aluminum hydroxide and saponins [Eisenbarth SC, Colegio OR, O’Connor W, Sutterwala FS, Flavell RA. Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants. Nature 2008;453(June (7198)):1122–6; Li H, Willingham SB, Ting JP, Re F. Cutting edge: inflammasome activation by alum and alum's adjuvant effect are mediated by NLRP3. J Immunol 2008;181(July (1)):17–21]. Inflammasome activation in vitro requires signaling of both the Toll-like receptor (TLR) and NLRP3 in antigen-presenting cells. Here we present a class of nanomaterials endowed with these two signals for rapid optimization of vaccine design. We constructed this system using a simple approach that incorporates lipopolysaccharides (LPS) onto the surface of nanoparticles constructed from a biocompatible polyester, poly(lactic-co-glycolic acid) (PLGA), loaded with antigen. We demonstrate that LPS-modified particles are preferentially internalized by dendritic cells compared to uncoated nanoparticles and the system, when administered to mice, elicits potent humoral and cellular immunity against a model antigen, ovalbumin. Wild-type macrophages pulsed with LPS-modified nanoparticles resulted in production of the proinflammatory cytokine IL-1β consistent with inflammasome activation. In comparison, NLRP3-deficient and caspase-1-deficient macrophages showed negligible production of IL-1β. Furthermore, when endocytosis and lysosomal destabilization were inhibited, inflammasome activity was diminished, supporting the notion that nanoparticles rupture lysosomal compartments and behave as ‘danger signals’ [Hornung V, Bauernfeind F, Halle A, Samstad EO, Kono H, Rock KL, et al. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat Immunol 2008;9(August (8)):847–56]. The generality of this vaccination approach is tested by encapsulation of a recombinant West Nile envelope protein and demonstrated by protection against a murine model of West Nile encephalitis. The design of such an antigen delivery mechanism