Next-generation genetic vaccines against malaria

Malaria is by far the world`s most serious tropical parasitic disease, which kills more people than any other communicable disease besides tuberculosis. This infection poses a public health problem today in more than 90 countries, inhabited by a total of some 2.5 billion people - 40% of the world`s population. "Global warming" and other climatic events help in further expanding the endemic areas thus exposing more people to the disease. In addition, the exponential increase in international travel has resulted in numerous infections in developed countries. These facts and the emergence of multi-drug resistant parasite strains are fuelling major efforts to develop effective malaria vaccines. However, these efforts are seriously hampered by the complex life cycle of the parasite, the antigenic variations, diversity of parasite strains and a number of sophisticated mechanisms used by the parasite to evade the host`s immune response. So far, conventional immunization strategies have yielded disappointing results, but the novel and revolutionary method of DNA-based vaccination has already proven its effectiveness against malaria infection in the mouse model. The aim of the proposed study is to improve our recently developed anti-malaria DNA vaccines, thereby reducing the amount of DNA required for protective immunity as well as the number of booster immunizations, a prerequisite for their application in developing countries. Furthermore, the question whether DNA vaccines confer protection via cytotoxic T cell responses and/or antibodies against malaria infection will be elucidated. Two well characterized target genes will be employed in the context of an advanced type of malaria DNA vaccine, i.e. a plasmid DNA vector driven by an alphavirus-based replicase. This vaccine will be delivered with a "gene gun", a device, which propels gold particles coated with the respective plasmid into the skin of the animals. This method of DNA vaccination has proven to be superior compared to intramuscular or intradermal needle injections. The replicase-based and the conventional construct will be evaluated for protective efficacy and longevity of protection in challenge experiments with live parasites. Additionally, modifications of the construct will be made, which either strongly enhance or completely abrogate antibody responses to investigate the protective principle behind DNA-based anti-malaria immunization.