DNA and RNA-based vaccines: principles, progress and prospects

DNA vaccines were introduced less than a decade ago but have already been a pplied to a wide range of infectious and malignant diseases, Here we review the current understanding of the mechanisms underlying the activities of t hese new vaccines. We focus on recent strategies designed to enhance their function including the use of immunostimulatory (CpG) sequences, dendritic cells (DC), co-stimulatory molecules and cytokine- and chemokine-adjuvants. Although genetic vaccines have been significantly improved, they may not b e sufficiently immunogenic for the therapeutic vaccination of patients with infectious diseases or cancer in clinical trials. One promising approach a imed at dramatically increasing the immunogenicity of genetic vaccines invo lves making them 'self-replicating'. This can be accomplished by using a ge ne encoding RNA replicase, a polyprotein derived from alphaviruses, such as Sindbis virus. Replicase-containing RNA vectors are significantly more imm unogenic than conventional plasmids, immunizing mice at doses as low as 0.1 mu g of nucleic acid injected once intramuscularly. Cells transfected with 'self-replicating' vectors briefly produce large amounts of antigen before undergoing apoptotic death. This death is a likely result of requisite dou ble-stranded (ds) RNA intermediates, which also have been shown to super-ac tivate DC. Thus, the enhanced immunogenicity of 'self-replicating' genetic vaccines may be a result of the production of pro-inflammatory dsRNA, which mimics an RNA-virus infection of host cells. (C) 1999 Elsevier Science Ltd . All rights reserved.