title: The preparation and characterization of PLG nanoparticles with an entrapped synthetic TLR7 agonist and their preclinical evaluation as adjuvant for an adsorbed DTaP vaccine.
abstract: The design of safe and potent adjuvants able to enhance and modulate antigen-specific immunity is of great interest for vaccine research and development. In the present study, negatively charged poly(lactide-co-glycolide) (PLG) nanoparticles have been combined with a synthetic immunepotentiator molecule targeting the Toll-like receptor 7. The selection of appropriate preparation and freeze-drying conditions resulted in a PLG-based adjuvant with well-defined and stable physico-chemical properties. The adjuvanticity of such nanosystem has later been evaluated in the mouse model with a diphtheria-tetanus-pertussis (DTaP) vaccine, on the basis of the current need to improve the efficacy of acellular pertussis (aP) vaccines. DTaP antigens were adsorbed onto PLG nanoparticles surface, allowing the co-delivery of TLR7a and multiple antigens through a single formulation. The entrapment of TLR7a into PLG nanoparticles resulted in enhanced IgG and IgG2a antibody titers. Notably, the immune potentiator effect of TLR7a was less evident when it was used in not-entrapped form, indicating that co-localization of TLR7a and antigens is required to adequately stimulate immune responses. In conclusion, the rational selection of adjuvants and formulation here described resulted as a highly valuable approach to potentiate and better tailor DTaP vaccine immunogenicity.
authors.affiliation: GSK Vaccines S.r.l., Via Fiorentina 1, 53100 Siena, Italy; Università di Siena, Via Aldo Moro 2, 53100 Siena, Italy. Electronic address: cristina.x.bruno@gsk.com.
authors.forename: Cristina
authors.initials: C
authors.lastname: Bruno
authors.affiliation: GSK Vaccines S.r.l., Via Fiorentina 1, 53100 Siena, Italy; Università degli Studi di Padova, Via Ugo Bassi 58b, 35121 Padova, Italy. Electronic address: va.agnolon@gmail.com.
authors.forename: Valentina
authors.initials: V
authors.lastname: Agnolon
authors.affiliation: GSK Vaccines S.r.l., Via Fiorentina 1, 53100 Siena, Italy. Electronic address: francesco.x.berti@gsk.com.
authors.forename: Francesco
authors.initials: F
authors.lastname: Berti
authors.affiliation: GSK Vaccines S.r.l., Via Fiorentina 1, 53100 Siena, Italy. Electronic address: simone.x.bufali@gsk.com.
authors.forename: Simone
authors.initials: S
authors.lastname: Bufali
authors.affiliation: GSK Vaccines, 350 Massachusetts Ave, Cambridge, 02139 MA, USA. Electronic address: derek.t.o'hagan@gsk.com.
authors.forename: Derek T
authors.initials: DT
authors.lastname: O'Hagan
authors.affiliation: GSK Vaccines S.r.l., Via Fiorentina 1, 53100 Siena, Italy. Electronic address: barbara.c.baudner@gsk.com.
authors.forename: Barbara C
authors.initials: BC
authors.lastname: Baudner
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000818:Animals; D022681:Diphtheria-Tetanus-acellular Pertussis Vaccines / Q000008:administration & dosage* / Q000276:immunology; D004353:Drug Evaluation, Preclinical; D007074:Immunoglobulin G / Q000097:blood; D019344:Lactic Acid / Q000737:chemistry*; D008562:Membrane Glycoproteins / Q000819:agonists*; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry*; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D051199:Toll-Like Receptor 7 / Q000819:agonists*
chemical_list: D000276:Adjuvants, Immunologic; D022681:Diphtheria-Tetanus-acellular Pertussis Vaccines; D007074:Immunoglobulin G; D008562:Membrane Glycoproteins; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid
keywords: Combination vaccines; PLG nanoparticles; Pertussis; Toll-like receptor 7 agonist; Vaccine formulation