title: TLR4 ligand formulation causes distinct effects on antigen-specific cell-mediated and humoral immune responses.
abstract: The formulation of TLR ligands and other immunomodulators has a critical effect on their vaccine adjuvant activity. In this work, the synthetic TLR4 ligand GLA was formulated with three distinct vaccine delivery system platforms (aqueous suspension, liposome, or oil-in-water emulsion). The effect of the different formulations on the adaptive immune response to protein subunit vaccines was evaluated in the context of a recombinant malaria antigen, Plasmodium berghei circumsporozoite protein (PbCSP). Antibody responses in vaccinated mice were similar for the different formulations of GLA. However, cell-mediated responses differed significantly depending on the adjuvant system; in particular, the emulsion formulation of the TLR4 ligand induced significantly enhanced cellular IFN-γ and TNF-α responses compared to the other formulations. The effects of differences in adjuvant formulation composition and physical characteristics on biological activity are discussed. These results illustrate the importance of formulation of immunostimulatory adjuvants (e.g. TLR ligands) on the resulting immune responses to adjuvanted vaccines and may play a critical role for combating diseases where T cell immunity is advantageous.
authors.affiliation: Infectious Disease Research Institute, 1616 Eastlake Avenue, Suite 400, Seattle, WA 98102, USA. Electronic address: cfox@idri.org.
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Fox
authors.forename: Magdalini
authors.initials: M
authors.lastname: Moutaftsi
authors.forename: Julie
authors.initials: J
authors.lastname: Vergara
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Desbien
authors.forename: Ghislain I
authors.initials: GI
authors.lastname: Nana
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Vedvick
authors.forename: Rhea N
authors.initials: RN
authors.lastname: Coler
authors.forename: Steven G
authors.initials: SG
authors.lastname: Reed
mesh_terms: D056704:Adaptive Immunity; D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D000953:Antigens, Protozoan / Q000276:immunology*; D005260:Female; D007111:Immunity, Cellular; D056724:Immunity, Humoral; D007371:Interferon-gamma / Q000276:immunology; D008024:Ligands; D017780:Malaria Vaccines / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010962:Plasmodium berghei / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000819:agonists* / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D022223:Vaccines, Subunit / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D000953:Antigens, Protozoan; D008024:Ligands; D017780:Malaria Vaccines; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D022223:Vaccines, Subunit; D007371:Interferon-gamma
keywords: Aqueous nanosuspension; Glucopyranosyl lipid adjuvant; Liposome; Oil-in-water emulsion; Th1-type immunity; Vaccine adjuvant formulation