Every day 2000 children die from malaria in Africa alone. The infection is transmitted from human to human by biting mosquitoes and remains one of the world’s most devastating diseases. Despite many years of effort a vaccine is still not available but is urgently needed, if we are to make an impact on this enormous problem.
Continual exposure can generate protection against malaria and can be acquired through an exposure to a high number of infectious mosquito bites. Parasites that are injected by a mosquito first migrate to the liver where they mature and then are released into the blood circulation and it is only here that they cause disease and fatal complications.
A very promising method for vaccination is to sufficiently weaken parasites such that they invade liver cells but then are not able to develop any further. It is, however, required that these attenuated parasites are still able to stimulate a good immune response in the liver. This can be achieved by irradiating the parasites or by genetically inactivating individual parasite genes that are active during the parasites growth in the liver. Researchers from Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands and LUMC, Leiden, the Netherlands, have now characterized a large number of parasite proteins (‘proteome’) that are present only during liver stage development and therefore are potential targets for inactivation.
The research groups had previously shown that protection in mice can be achieved by vaccinating mice with a rodent malaria which had one of these liver stage genes removed, specifically p36p. Moreover, the protection was long lasting and virtually complete. Now, these same researchers from Nijmegen and Leiden have succeeded in making the first critical transition from the rodent system to humans by inactivating the equivalent gene (p52) in the most important human malaria parasite, P. falciparum. Similar to the results with the rodent parasite, these human parasites are unable to develop in liver cells. This is the first time that genetic modification of a human parasite results in its growth arrest in a liver cell, opening up exciting possibilities for its use as a human vaccine.
These studies form part of a collaborative project with the American company Sanaria, whose sole purpose is develop a whole organism malaria parasite vaccine for use in humans, and is funded by TI-Pharma. These studies show how results obtained in rodent models of malaria can be pipelined to form the basis for clinical development of anti-malaria vaccines in humans.
- Lasonder et al. Proteomic Profiling of Plasmodium Sporozoite Maturation Identifies New Proteins Essential for Parasite Development and Infectivity. PLoS Pathogens, 2008; 4 (10): e1000195 DOI: 10.1371/journal.ppat.1000195
- van Schaijk et al. Gene Disruption of Plasmodium falciparum p52 Results in Attenuation of Malaria Liver Stage Development in Cultured Primary Human Hepatocytes. PLoS ONE, 2008; 3 (10): e3549 DOI: 10.1371/journal.pone.0003549
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