title: CD205 antigen targeting combined with dendritic cell recruitment factors and antigen-linked CD40L activation primes and expands significant antigen-specific antibody and CD4(+) T cell responses following DNA vaccination of outbred animals.
abstract: Dendritic cell antigen targeting primes robust immune responses in mouse models. Optimizing this immunization strategy in the actual hosts that require protection will advance development of efficacious contemporary vaccines. In a proof-of-concept study, we tested the immunogenicity of a single, low dose of a novel multi-component DNA construct expressing a CD205-targeted antigen fused to a CD40L minimal functional domain for linked DC activation. The DNA construct was formulated with DNA-encoded Flt3L and GM-CSF for DC recruitment and the formulation was evaluated in MHC class II-matched calves. Immunization of the calves with the CD205 antigen-targeting construct mixed with the cytokine constructs induced significant IFN-γ-secreting CD4(+) T-cells, CD4(+) T-cell proliferation, and antibody responses detectable within one week post-immunization. CD205 antigen-targeting significantly expanded IFN-γ-secreting CD4(+) T-cells, CD4(+) T-cell proliferation, and IgG antibody responses three weeks post-immunization. Nineteen weeks post-priming, the IFN-γ-secreting CD4(+) T-cells, CD4(+) T-cell proliferation, and the IgG titers were waning, but they remained significant. Following boosting at nineteen weeks post-immunization, the immune responses primed by the CD205-targeted antigen underwent rapid recall and the mean response tripled within one week post-boost. Comparative analysis of the immune responses observed one week post-priming versus the responses detected one week post-boost revealed that the average number of the IFN-γ-secreting CD4(+) T-cells observed in the calves immunized with the CD205 antigen targeting construct increased five-fold, the mean CD4(+) T-cell proliferation increased three-fold, whereas the mean IgG antibody titer increased two hundred-fold. These promising outcomes support testing the protective efficacy of CD205-targeted antigens in the calf model.
authors.affiliation: Department of Veterinary Pathobiology, Texas A&M University, College Station, TX 77843, USA.
authors.forename: Leo M
authors.initials: LM
authors.lastname: Njongmeta
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Bray
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Davies
authors.forename: William C
authors.initials: WC
authors.lastname: Davis
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Howard
authors.forename: Jayne C
authors.initials: JC
authors.lastname: Hope
authors.forename: Guy H
authors.initials: GH
authors.lastname: Palmer
authors.forename: Wendy C
authors.initials: WC
authors.lastname: Brown
authors.forename: Waithaka
authors.initials: W
authors.lastname: Mwangi
mesh_terms: D042322:Anaplasma marginale / Q000276:immunology; D000818:Animals; D000917:Antibody Formation; D015703:Antigens, CD / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology; D001425:Bacterial Outer Membrane Proteins / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D023201:CD40 Ligand / Q000276:immunology*; D002417:Cattle; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000276:immunology*; D004306:Dose-Response Relationship, Immunologic; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology; D057809:HEK293 Cells; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D007371:Interferon-gamma / Q000276:immunology; D037181:Lectins, C-Type / Q000276:immunology*; D008213:Lymphocyte Activation; D008297:Male; D008565:Membrane Proteins / Q000276:immunology; D015778:Minor Histocompatibility Antigens; D011956:Receptors, Cell Surface / Q000276:immunology*; D019444:Vaccines, DNA / Q000276:immunology*
chemical_list: D015703:Antigens, CD; D001425:Bacterial Outer Membrane Proteins; C093569:DEC-205 receptor; D007074:Immunoglobulin G; D037181:Lectins, C-Type; D008565:Membrane Proteins; D015778:Minor Histocompatibility Antigens; D011956:Receptors, Cell Surface; D019444:Vaccines, DNA; C084881:flt3 ligand protein; C449089:major surface protein 1a, Anaplasma; D023201:CD40 Ligand; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor