* To further investigate the vaccine potential of SALSA, STARP, LSA1 and LSA3.
* To improve our understanding of the mechanisms mediating protection against P. falciparum MPES in humans.
* To investigate the potential of 10 novel MPES genes and to choose those which deserve further characterization and immunogenicity studies.
A strengthened network of EC and DC partners, with a better understanding of the critical effector mechanisms that protect humans against P. falciparum pre-erythrocytic stage parasites. From this improved understanding we expect to develop a rational strategy for human MPES vaccine development.
* Using the 4 lead antigens (Ags) SALSA, LSA1, STARP and LSA3, whose antigenicity is established, we will employ a series of antigen-presentation systems, namely lipopeptides, multiple antigen lipopep-tides, recombinant Ags adsorbed to microparticles, DNA-based immunization, in order to optimize the conditions under which defence mechanisms are induced in chimps, in Aotus against P. falciparum and in mice against P. yoelii. Where necessary improved recombinant expression systems will also be evaluated.
* Perform analysis of B, Th, CTL responses, and identify antigens targeted by mechanisms effective under in vitro conditions, so as to provide an understanding of the basis of protection and therefore develop adapted formulations.
* Develop improved in vivo and in vitro screening systems to evaluate the 4 lead Ags. Compare antigen specific immune responses in humans and in chimpanzees immunized with irradiated sporozoites. Analyze the relationship between immune responses and protective status in individuals exposed in endemic areas. Analyze in vitro with the human and chimpanzee hepatocyte model the various effector mechanisms directed to these antigens. Immunize and challenge chimpanzees, Aotus and mice. Additional studies in rodents, in immunocompromised animals reconstituted with human hepatocytes, and in exposed populations, are aimed at supplying an understanding of the immunological basis of protection in natural host-parasite combinations (P. berghei in Thamnomys, P. falciparum in humans and human hepatocytes) and particularly studying CTL activity.
* Employ the conditions of immunization defined in the above steps to investigate the potential of a further 10 novel antigens.
* Extend the "best" antigens and presentation systems, identified in these studies, mostly in chimpanzees and Aotus, to a larger groups of Aotus so as to gather statistically significant data.
Funding SchemeCSC - Cost-sharing contracts
2288 GJ Rijswijk Zh
2000 Anvers /Antwerpen
6500 HB Nijmegen