title: Pulmonary delivery of DNA encoding Mycobacterium tuberculosis latency antigen Rv1733c associated to PLGA-PEI nanoparticles enhances T cell responses in a DNA prime/protein boost vaccination regimen in mice.
abstract: During persistent infection and hypoxic-stress, Mycobacterium tuberculosis (Mtb) expresses a series of Mtb latency antigens. The aim of this study was to evaluate the immunogenicity of a DNA vaccine encoding the Mtb latency antigen Rv1733c and to explore the effect of pulmonary delivery and co-formulation with poly (d,l-lactide-co-glycolide) (PLGA)-polyethyleneimine (PEI) nanoparticles (np) on host immunity. Characterization studies indicated that PLGA-PEI np kept their nanometer size after concentration and were positively charged. The np were able to mature human dendritic cells and stimulated them to secrete IL-12 and TNF-alpha comparable to levels observed after lipopolysaccharide (LPS) stimulation. Mtb latency antigen Rv1733c DNA prime combined with Rv1733c protein boost enhanced T cell proliferation and IFN-gamma secretion in mice in response to Rv1733c and Mtb hypoxic lysate. Rv1733c DNA adsorbed to PLGA-PEI np and applied to the lungs increased T cell proliferation and IFN-gamma production more potently compared to the same vaccinations given intramuscularly. The strongest immunogenicity was obtained by pulmonary priming with np-adsorbed Rv1733c DNA followed by boosting with Rv1733c protein. These results confirm that PLGA-PEI np are an efficient DNA vaccine delivery system to enhance T cell responses through pulmonary delivery in a DNA prime/protein boost vaccine regimen.
authors.affiliation: Division of Drug Delivery Technology, Leiden/Amsterdam Center for Drug Research, 2300 RA Leiden, The Netherlands. m.bivas@lacdr.leidenuniv.nl
authors.forename: Maytal
authors.initials: M
authors.lastname: Bivas-Benita
authors.forename: May Young
authors.initials: MY
authors.lastname: Lin
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Bal
authors.forename: Krista E
authors.initials: KE
authors.lastname: van Meijgaarden
authors.forename: Kees L M C
authors.initials: KL
authors.lastname: Franken
authors.forename: Annemieke H
authors.initials: AH
authors.lastname: Friggen
authors.forename: Hans E
authors.initials: HE
authors.lastname: Junginger
authors.forename: Gerrit
authors.initials: G
authors.lastname: Borchard
authors.forename: Michèl R
authors.initials: MR
authors.lastname: Klein
authors.forename: Tom H M
authors.initials: TH
authors.lastname: Ottenhoff
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000494:pharmacology; D000280:Administration, Inhalation; D000818:Animals; D000942:Antigens, Bacterial / Q000235:genetics* / Q000276:immunology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D006801:Humans; D007117:Immunization, Secondary; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D019344:Lactic Acid / Q000008:administration & dosage / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D009169:Mycobacterium tuberculosis / Q000235:genetics* / Q000276:immunology; D053758:Nanoparticles / Q000008:administration & dosage; D011094:Polyethyleneimine / Q000008:administration & dosage / Q000494:pharmacology; D011100:Polyglycolic Acid / Q000008:administration & dosage / Q000494:pharmacology; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D013601:T-Lymphocytes / Q000276:immunology*; D032581:Tuberculosis Vaccines / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D019444:Vaccines, DNA / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology*; D022223:Vaccines, Subunit / Q000008:administration & dosage / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D000942:Antigens, Bacterial; D032581:Tuberculosis Vaccines; D014409:Tumor Necrosis Factor-alpha; D019444:Vaccines, DNA; D022223:Vaccines, Subunit; D018664:Interleukin-12; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D007371:Interferon-gamma; D011094:Polyethyleneimine