nomenon [26]. Indeed, Krieg et al. [21] showed that the elimination of the CpG in a particular ODN invariably abolished immune stimulation, but changes in the ODN sequences that did not affect the CpG or the flanking bases did not alter the immuno- stimulatory (IS) effect. Furthermore, they extended the initial observations of the IS effects to non-palindromic CpG-enriched ODN [21]. Subsequent studies showed that CpG-enriched ODN also induce the secretion of IL-6 and IL-12 [19] and IFN-a [6, 27]. By adding or deleting various IS sequences (ISS)-ODN to or from different pDNAs, it was demonstrated that the ISS have a pivotal role in the induction of the subsequent immune response to the gene product in gene-vaccinated animals. The enhanced Thl immune response induced by gene vaccination is the consequence of the activation of the innate immune response by the ISS in the pDNA backbone [30, 31], rather than the low dose of intracellularly produced antigen. The cell activation products induced by the ISS, i. e. , IFN-a [3], IFN-~ [43], IL-12 [37], and IL-18 [25], are established inducers of IFN-y synthesis and promote the differentiation of naive T helper cells to Thl lym- phocytes. Thus, the ISS activate the precise innate cytokine network required to pro- mote Thl differentiation (see Fig. 1). In a recent study it was demonstrated that this ap- proach is also applicable to a protein antigen.