The comparative efficacy of CTLA-4 and L-selectin targeted DNA vaccines inmice and sheep

The access of antigens to antigen presenting cells (APCs) appears to be a r ate-limiting step in the generation of immune responses to DNA vaccines. Th e cytotoxic T lymphocyte antigen 4 (CTLA-4) and L-selectin represent attrac tive ligands for use in the targeting of antigen to APCs and lymph nodes. C TLA-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 s urface of high endothelial venule cells. DNA vaccines encoding human immuno globulin (HIg), fused to either CTLA-4 or L-selectin. have been shown to ge nerate up to 10,000-fold higher anti-HIg antibody responses than DNA vaccin es encoding HIg alone. In this study, the ability of CTLA-4 or L-selectin m ediated targeting to enhance the humoral immune response to an alternate va ccine antigen was investigated. DNA vaccines encoding CTLA-4-HIg and L-sele ctin-HIg fused to the host-protective 45W antigen from Taenia oris were con structed. In BALB/c mice. the L-selectin targeted vaccine did not improve e ither the magnitude or speed of antibody responses of vaccinated mice. In c ontrast, the CTLA-4 targeted DNA vaccine generated 45W-specific antibody re sponses which were up to 30-fold higher than those achieved with non-target ed DNA vaccination. The kinetic of the antibody response generated followin g CTLA-4 targeted DNA vaccination was also significantly faster than that a chieved with non-targeted DNA vaccination, or with adjuvanted protein vacci nation. Vaccination of outbred sheep with DNA vaccines expressing either mu rine or ovine CTLA-4 targeted antigen failed to enhance immune responses. T hese findings indicate that CTLA-4 targeting may find application in the im provement of DNA vaccines, but requires further development for application s in large animal species. (C) 2001 Published by Elsevier Science Ltd.