Discussion

Genetic manipulation of Plasmodium parasite has considerably improved our understanding of parasite gene function and revealed many novel host-parasite interactions underlie malaria pathology. Genetically modified malaria-parasites are now also being used directly as vaccines against malaria and the LUMC were one of first groups to develop the concept of immunization with genetically attenuated parasites (GAPs). Together with our partners we have established a roadmap that goes from GAP immunization studies in rodent models, through pre-clinical testing and into vaccine manufacture and Phase 1/2 clinical evaluation. We are currently engaged in GAP vaccine trials that are now being conducted in volunteers in the Netherlands. The procedures for GAP selection and testing as well as the safety and efficacy trial will be presented. In addition, we are creating transgenic malaria parasites that express foreign genes (e.g. fluorescent and luminescent proteins) that are also being used to advance malaria sub-unit vaccine development. How transgenic malaria parasites are used, in vitro and in vivo, to determine protective efficacy of different Plasmodium antigens and vaccination strategies and to determine immunological correlates of protection will be discussed. Chimeric rodent parasites expressing P. falciparum or P. vivax antigens are also being used to evaluate and rank order human malaria vaccines before their advancement to clinical testing and will also be described.