Incorporation of Immunomodulators into Plasmid DNA Vaccines

The success of candidate vaccines against infectious disease depends on their ability to activate components of the immune response (innate, cellular, and/or humoral) appropriate to the correlates of protection identified for the particular pathogen. Recombinant DNA technology has provided the opportunity to rationally design vaccines based upon the identified protective antigens, and also to modulate the type and magnitude of the immune response by the incorporation of genetic adjuvants. These may include cytokines, chemokines, costimulatory molecules, or hemopoietic growth factors (see ref. 1 ). The choice of immunomodulatory molecule reflects the polarization of the immune response (Th1 and cell-mediated or Th2 and antibody) selected to eliminate the particular pathogen by the vaccine candidate. The presence of IL-12, IL-15, IL-18, or interferon-gamma (IFN-γ) are critical in the development of Th1 responses that are directed toward cell-mediated immunity (2 ), and the presence of IL-4, IL-5, and IL-10 are critical in the development of Th2 responses that are directed toward antibody production (2 ). For weakly immunogenic antigens, the incorporation of genes that code for pro-inflammatory cytokines (e.g., IL-1α, TNF-α, or TGF-β) or costimulatory molecules (CD80, CD86, and CD40-ligand) may provide maturation signals to antigen-presenting cells (APC) to enhance their ability to present vaccine antigens, and result in an increased adaptive immune response (3 ,4 ). More recently, cytokines and chemokines, including granulocyte-macrophage colony-stimulating factor (GM-CSF), monocyte chemotactic proteins (MCPs) and macrophage inflammatory proteins (MIPs), have been incorporated into vaccines in lieu of their potential to increase recruitment of blood-borne dendritic cells and monocytes to interstitial sites of vaccine delivery (5 ).