title: TLR9-targeted biodegradable nanoparticles as immunization vectors protect against West Nile encephalitis.
abstract: Vaccines that activate humoral and cell-mediated immune responses are urgently needed for many infectious agents, including the flaviviruses dengue and West Nile (WN) virus. Vaccine development would be greatly facilitated by a new approach, in which nanoscale modules (Ag, adjuvant, and carrier) are assembled into units that are optimized for stimulating immune responses to a specific pathogen. Toward that goal, we formulated biodegradable nanoparticles loaded with Ag and surface modified with the pathogen-associated molecular pattern CpG oligodeoxynucleotides. We chose to evaluate our construct using a recombinant envelope protein Ag from the WN virus and tested the efficiency of this system in eliciting humoral and cellular responses and providing protection against the live virus. Animals immunized with this system showed robust humoral responses polarized toward Th1 immune responses compared with predominately Th2-biased responses with the adjuvant aluminum hydroxide. Immunization with CpG oligodeoxynucleotide-modified nanoparticles resulted in a greater number of circulating effector T cells and greater activity of Ag-specific lymphocytes than unmodified nanoparticles or aluminum hydroxide. Ultimately, compared with alum, this system offered superior protection in a mouse model of WN virus encephalitis.
authors.affiliation: Department of Biomedical Engineering, Yale University, New Haven, CT 06511, USA.
authors.forename: Stacey L
authors.initials: SL
authors.lastname: Demento
authors.forename: Nathalie
authors.initials: N
authors.lastname: Bonafé
authors.forename: Weiguo
authors.initials: W
authors.lastname: Cui
authors.forename: Susan M
authors.initials: SM
authors.lastname: Kaech
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Caplan
authors.forename: Erol
authors.initials: E
authors.lastname: Fikrig
authors.forename: Michel
authors.initials: M
authors.lastname: Ledizet
authors.forename: Tarek M
authors.initials: TM
authors.lastname: Fahmy
mesh_terms: D000818:Animals; D001360:Avidin / Q000008:administration & dosage / Q000378:metabolism; D001672:Biocompatible Materials / Q000008:administration & dosage*; D001710:Biotin / Q000008:administration & dosage / Q000378:metabolism; D002478:Cells, Cultured; D004330:Drosophila; D018390:Gene Targeting; D005822:Genetic Vectors / Q000008:administration & dosage / Q000276:immunology*; D051379:Mice; D053758:Nanoparticles / Q000008:administration & dosage*; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism / Q000821:virology; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism / Q000821:virology; D051217:Toll-Like Receptor 9 / Q000378:metabolism*; D014901:West Nile Fever / Q000276:immunology / Q000517:prevention & control*; D053060:West Nile Virus Vaccines / Q000008:administration & dosage* / Q000276:immunology; D014902:West Nile virus / Q000235:genetics / Q000276:immunology*
chemical_list: D001672:Biocompatible Materials; C408982:CPG-oligonucleotide; D009838:Oligodeoxyribonucleotides; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D053060:West Nile Virus Vaccines; D001360:Avidin; D001710:Biotin