Session 48Poster Presentations Vaccine Adjuvants Session Day and Time: Tuesday 1:30 - 3:30 pm Room: Hall D
399 IL-15 Enhances both Prophylactic and Immunotherapeutic Vaccines When Used in Combination with HIV-1 DNA Vaccines D. B. Weiner*1, M. Kutzler1, T. Robinson1, M. Lewis2, R. R. MacGregor3, J. D. Boyer1 1Univ of Pennsylvania, Philadelphia; 2Southern Res Inst, Frederick, MD; and 3Hosp of Univ of Pennsylvania, Philadelphia
Background: We have tested HIV-1 DNA vaccines in both non-human primates studies as well as phase I clinical studies. We have demonstrated HIV-1 DNA vaccines are safe and immunogenic. However, these studies have also demonstrated that the induced HIV-1 specific CD8 cellular immune response must be increased above the current obtainable levels.
Method: For that reason we have been looking at cytokines and co-stimulatory molecules as immune modulating molecules with the purpose of expanding the CD8 immune response. In particular, IL-15 has demonstrated the ability to expand CD8 antigen specific lymphocytes. Nevertheless, the native genomic IL-15 structure does not lead to high levels of IL-15 expression due to post-transcriptional regulation. Accordingly, we changed the IL-15 leader sequence to obtain more efficient expression. We were able to increase the level of protein expression by 50 to 100 fold. In combination with our HIV-1 DNA vaccines IL-15 dramatically expands CD8 effector function in vivo. In fact, we observed increases in functional CTL responses as well as CD8 specific secretion of INF-gamma. Indeed, quantitative analysis, as assessed by ELISpot and intracellular staining for IFN-gamma, demonstrated approximately a 15-fold increase in the vaccine specific CD8 compartment. In addition, preliminary primate studies have also demonstrated enhanced immunogenicity. Also, IL-15 tested in vitro with PBMCs isolated from individuals seropositive for HIV-1 demonstrated an enhanced HIV-1 CD8 response. Furthermore, some of the donors had compromised immune responses; yet IL-15, in combination with CD40L, restored the CD8 effector function. This latter finding indicates that IL-15, when used in combination with CD40L, is an excellent choice as an immunotherapeutic treatment. Our goal will be to assess this combination in the clinical setting.
