Cytokine and costimulatory factor-encoding plasmids as adjuvants for DNA vaccination

The induction of a potent and long-lasting immunity is one of the most important elements to consider in developing an effective vaccine. DNA vaccines induce markedly stronger CD8(+) cytotoxic T lymphocyte (CTL) activity than do traditional peptide vaccines through their particular mechanism of antigen presentation mediated by MHC class I molecules. Induction of CTL specific to pathogenic viruses is thought to provide a reliable means of protecting a host from infection and halting disease progression, as these cells can directly recognize and lyse infected cells. However, in most of the early studies showing induction of pathogen-specific CTL, antigen-encoding immunogenic DNA alone was used and DNA vectors encoding immunomodulating molecules were not considered. It now appears that various types of immunomodulatory molecules such as cytokines (IL-1 [1], IL-2 [2], IL-12 [3], IFN-γ [4], IL-7 [5-7], and GM-CSF [8,9]), chemokines (TCA-3 [10], RANTES [11], MIP-1 [11]), and costimulatory molecules (CD40L [12], B7-1 [13] and B7-2 [14]) could enhance or modify the specific immune responses elicited by DNA immunization (see Table 1). Table 1 Summary of Effects of Cytokines after Conventional Vaccination and of Expression Plasmids following DNA Immunization Immunomodulatory Molecules Effect Ref. A. Cytokine proteins IL-1 Antibody (Ab) ↑ (23,24) IL-2 Ab ↑ (2,25,26) IL-12 TH1(DTH) ↑ (3) IFN-γ Ab, DTH ↑ (4,25,27) GM-CSF Ab ↑ (28,29) B. Expression plasmids IL-12 CTL ↑(i.m. and i.n.) (15,21,22,30) DTH ↑(i.m. and i.n.) (5,21) Ab →(i.m. and i.n.) (15,22) GM-CSF Ab ↑(i.m.) (9,18,22 CTL ↑(i.m.) (18) (3)H-TdR uptake ↑(i.m.) (9) TCA3 CTL ↑(i.m.) (31) DTH ↑(i.m.) (31) Ab →(i.m.) (31) B7-1 CTL →(i.m.) (19) DTH →(i.m.) (19) Ab →(i.m.) (19) B7-2 CTL ↑(i.m.) (19) DTH ↑(i.m.) (19) Ab →(i.m.) (19) CD40(L) Ab →(i.m.) (A. Ihata et al., Unpublished data) CTL ↑(i.m.) (A. Ihata et al., Unpublished data) i.m., intramuscular administration; i.n., intranasal administration; Ab, antibody production; DTH, delayed type hypersensitivity; (3)H-TdR, incorporation of (3)H-Thymidine; ↑, activated immune response.