title: Fibronectin EDA and CpG synergize to enhance antigen-specific Th1 and cytotoxic responses.
abstract: Subunit vaccines, employing purified protein antigens rather than intact pathogens, require the addition of adjuvants for enhanced immunogenicity with a correct balance between strong activation of the immune system and low toxicity. Here we show that the endogenous (i.e., autologous) non-toxic TLR4 agonist extra domain A type III repeat of fibronectin (FNIII EDA) can synergize with the exogenous (i.e., bacterial), toxic-at-high-dose, TLR9 agonist CpG to induce efficient cellular immune responses while keeping the dose of CpG low. The efficacy of the combined TLR agonists, even at half-doses, led to stronger dendritic cell activation, enhanced cytotoxic T lymphocyte activation as well as stronger humoral response, compared to the individual agonists given at full doses. Immune cells induced after vaccination with the co-adjuvanted formulation could mediate tumor regression in an E.G7-OVA tumor model, and eradicate circulating hepatitis B virus (HBV) in a transgenic HBV model. Together, these results show that endogenous TLR agonists, such as variants of FNIII EDA, can synergize with exogenous TLR ligands, such as CpG, and strongly enhance cellular immune responses, while improving their safety profile.
authors.affiliation: Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
authors.forename: Ziad
authors.initials: Z
authors.lastname: Julier
authors.affiliation: Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
authors.forename: Alexandre
authors.initials: A
authors.lastname: de Titta
authors.affiliation: Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
authors.forename: Alizée J
authors.initials: AJ
authors.lastname: Grimm
authors.affiliation: Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Simeoni
authors.affiliation: Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland; Institute for Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland; Institute for Molecular Engineering, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Melody A
authors.initials: MA
authors.lastname: Swartz
authors.affiliation: Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland; Institute for Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland; Institute for Molecular Engineering, University of Chicago, Chicago, IL 60637, USA. Electronic address: jhubbell@uchicago.edu.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Hubbell
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000818:Animals; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology; D004195:Disease Models, Animal; D005353:Fibronectins / Q000737:chemistry / Q000276:immunology*; D006509:Hepatitis B / Q000276:immunology / Q000821:virology; D017325:Hepatitis B Vaccines / Q000008:administration & dosage / Q000276:immunology*; D006515:Hepatitis B virus / Q000276:immunology; D007111:Immunity, Cellular; D056724:Immunity, Humoral; D051379:Mice; D008822:Mice, Transgenic; D009838:Oligodeoxyribonucleotides / Q000276:immunology*; D051192:Receptors, Pattern Recognition; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000819:agonists* / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000819:agonists / Q000276:immunology; D014611:Vaccination
chemical_list: D000276:Adjuvants, Immunologic; C408982:CPG-oligonucleotide; D019496:Cancer Vaccines; D005353:Fibronectins; D017325:Hepatitis B Vaccines; D009838:Oligodeoxyribonucleotides; D051192:Receptors, Pattern Recognition; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9
keywords: Adaptive immunity; Adjuvant; Cancer vaccine; CpG; FNIII EDA; Hepatitis B virus; Pattern recognition receptors; Toll-like receptors