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ATTMAL


MALARIA

New Genetic Technologies: Applications to Generate Attenuated Malaria Vaccines
Framework programme:
5
Project number:
ICA4-CT-1999-10004
EC contribution:
€ 1 492 640
Duration:
36 months
Type:
RS
Starting date:
1 March 2000

Summary:

Malaria vaccines are urgently required. Recombinant, multi-component cocktail vaccines are currently favoured. Using very recent technological advances, this programme revives the concept of attenuated parasites as vaccines. It brings together for the first time leading EU and African groups to develop methodologies allowing for the design and creation of parasites with properties desirable in such a vaccine. The ultimate delivery of such a vaccine may be as sexually incompetent, genetically restricted parasites, or as transmissible self-spreading forms. For whichever route, certain fundamental pre-conditions must be met, and these are the major focus of this proposal. Systems will be developed to provide 1) auxotrophic parasites, 2) sequential unrestricted genetic manipulation of parasites, 3) axenic culture, 4) parasite knockouts for specific genes, and 5) immuno-potentiated parasites through heterologous gene expression. In combination with a dialogue across scientific and public interests, this programme will enable the partnership to provide a clear assessment of the feasibility of vaccination with genetically modified malaria within three years.

Objectives:

Using the particular advantages offered by working with human, primate and rodent malaria parasites, technologies will be developed that permit the rational design and production of live attenuated vaccines. Such technologies are also vital to the general investigation of malaria parasite biology, vaccine research, drug discovery and mechanisms of resistance. This will be achieved by:

1) developing systems for the improved genetic manipulation of Plasmodium based on negative selection that allow the reuse of the limited number of effective selectable markers

2) developing auxotrophic Plasmodium parasites dependent upon an exogenous supply of uracil by targeted deletion of the cloned parasite ura 3 gene

3) developing rationally axenic culture of malaria parasites, based upon detailed measurements of the intracellular environment of the infected erythrocyte

4) developing genetically engineered Plasmodium that is growth-impaired through a strategic reduction in its ability to produce protein

5) initiating a discussion about genetically engineered malaria parasites in Africa that will further debate the application of attenuated parasites and liase with a similar forum in Europe.

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