title: The comparative efficacy of CTLA-4 and L-selectin targeted DNA vaccines in mice and sheep.
abstract: The access of antigens to antigen presenting cells (APCs) appears to be a rate-limiting step in the generation of immune responses to DNA vaccines. The cytotoxic T lymphocyte antigen 4 (CTLA-4) and L-selectin represent attractive ligands for use in the targeting of antigen to APCs and lymph nodes. CTLA-4 binds with high affinity to the B7 membrane antigen on APCs, while L-selectin functions as a lymphocyte homing marker and binds to CD34 on the surface of high endothelial venule cells. DNA vaccines encoding human immunoglobulin (HIg), fused to either CTLA-4 or L-selectin, have been shown to generate up to 10,000-fold higher anti-HIg antibody responses than DNA vaccines encoding HIg alone. In this study, the ability of CTLA-4 or L-selectin mediated targeting to enhance the humoral immune response to an alternate vaccine antigen was investigated. DNA vaccines encoding CTLA-4-HIg and L-selectin-HIg fused to the host-protective 45W antigen from Taenia ovis were constructed. In BALB/c mice, the L-selectin targeted vaccine did not improve either the magnitude or speed of antibody responses of vaccinated mice. In contrast, the CTLA-4 targeted DNA vaccine generated 45W-specific antibody responses which were up to 30-fold higher than those achieved with non-targeted DNA vaccination. The kinetic of the antibody response generated following CTLA-4 targeted DNA vaccination was also significantly faster than that achieved with non-targeted DNA vaccination, or with adjuvanted protein vaccination. Vaccination of outbred sheep with DNA vaccines expressing either murine or ovine CTLA-4 targeted antigen failed to enhance immune responses. These findings indicate that CTLA-4 targeting may find application in the improvement of DNA vaccines, but requires further development for applications in large animal species.
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, The Royal Melbourne Hospital, Parkville, Victoria 3050, Melbourne, Australia. drew@wehi.edu.au
authors.forename: D R
authors.initials: DR
authors.lastname: Drew
authors.forename: J S
authors.initials: JS
authors.lastname: Boyle
authors.forename: A M
authors.initials: AM
authors.lastname: Lew
authors.forename: M W
authors.initials: MW
authors.lastname: Lightowlers
authors.forename: P J
authors.initials: PJ
authors.lastname: Chaplin
authors.forename: R A
authors.initials: RA
authors.lastname: Strugnell
mesh_terms: D000069594:Abatacept; D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis; D000909:Antibodies, Helminth / Q000096:biosynthesis; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology*; D000947:Antigens, Helminth / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D060908:CTLA-4 Antigen; D002460:Cell Line; D003551:Cysticercosis / Q000517:prevention & control / Q000662:veterinary; D005260:Female; D007115:Immunization Schedule; D018796:Immunoconjugates; D007136:Immunoglobulins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D007273:Injections, Intramuscular; D019041:L-Selectin / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D012756:Sheep; D012757:Sheep Diseases / Q000517:prevention & control; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D000974:Antibodies, Antinuclear; D000909:Antibodies, Helminth; D015703:Antigens, CD; D000943:Antigens, Differentiation; D000947:Antigens, Helminth; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D007136:Immunoglobulins; D011993:Recombinant Fusion Proteins; D019444:Vaccines, DNA; D019041:L-Selectin; D000069594:Abatacept