title: Targeting the deep lungs, Poloxamer 407 and a CpG oligonucleotide optimize immune responses to Mycobacterium tuberculosis antigen 85A following pulmonary delivery.
abstract: The current Bacille Calmette-Guérin vaccine provides variable protection against tuberculosis and new vaccination approaches are urgently needed. Pulmonary vaccination could be the best way to induce a protective immunity against Mycobacterium tuberculosis as it targets its natural site of infection. The aim of this study was to investigate the potential of Poloxamer 407 (P407) combined with a CpG oligonucleotide (CpG) to enhance immune responses to M. tuberculosis antigen 85A (Ag85A) following pulmonary delivery in BALB/c mice. An additional goal of this study was to localize the optimal delivery site of Ag85A within the lungs for generating the most intense immunity. We also investigated the capacity of P407 to prolong the residence time of the antigen within the lungs and we studied the safety of the adjuvants following pulmonary delivery. Targeting the antigen to the deep lungs produced more intense specific immune responses than targeting it to the upper airways. P407 and CpG further increased humoral immune responses and splenocyte proliferation in vitro. CpG strongly increased the Th-1 immune response with high IgG2a/IgG1 ratio, high IFN-γ and TNF-α productions by spleen mononuclear cells in vitro. P407 tended to induce a Th-2 response, as indicated by the slight decrease in IgG2a/IgG1 ratio and the slight increase in IL-5 levels. The combination of P407 and CpG produced the highest Th-1 and Th-17 responses by generating IFN-γ, TNF-α, IL-2, and IL-17A cytokines. Targeting the antigen to the deep lungs and the presence of P407 increased the residence time of the antigen within the lungs. This might explain the enhancement of immune responses induced by these factors. CpG did not induce inflammation in the lungs while P407 produced a reversible alteration of the alveolo-capillary barrier. Adding CpG to P407 did not further increase this alteration of the alveolo-capillary barrier. In conclusion, delivery of Ag85A formulated in a combination of P407 and CpG to the deep lungs induced strong immune responses, with a polyfunctional T cells phenotype.
authors.affiliation: Université catholique de Louvain, Louvain Drug Research Institute, Pharmaceutics and Drug Delivery Research Group, Brussels, Belgium.
authors.forename: Julie
authors.initials: J
authors.lastname: Todoroff
authors.forename: Bernard
authors.initials: B
authors.lastname: Ucakar
authors.forename: Malory
authors.initials: M
authors.lastname: Inglese
authors.forename: Sophie
authors.initials: S
authors.lastname: Vandermarliere
authors.forename: Catherine
authors.initials: C
authors.lastname: Fillee
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Renauld
authors.forename: Kris
authors.initials: K
authors.lastname: Huygen
authors.forename: Rita
authors.initials: R
authors.lastname: Vanbever
mesh_terms: D000217:Acyltransferases / Q000276:immunology*; D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology*; D002478:Cells, Cultured; D016503:Drug Delivery Systems / Q000379:methods; D005260:Female; D007111:Immunity, Cellular / Q000187:drug effects / Q000276:immunology*; D008168:Lung / Q000187:drug effects / Q000276:immunology* / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage / Q000276:immunology*; D020442:Poloxamer / Q000008:administration & dosage
chemical_list: D000942:Antigens, Bacterial; C408982:CPG-oligonucleotide; D009838:Oligodeoxyribonucleotides; D020442:Poloxamer; D000217:Acyltransferases; C112580:antigen 85A, Mycobacterium tuberculosis