Scientists have developed a novel immunisation method that will induce fast and effective protection in humans against the life-threatening malaria parasite, Plasmodium falciparum. The findings of associate professor Laurent Renia from A*STAR's Singapore Immunology Network (SIgN) and his counterparts in the Netherlands and France were published in the prestigious New England Journal of Medicine on 30 July 2009 under the title, 'Protection against a malaria challenge by sporozoite inoculation'.

This discovery could contribute significantly to the development of an effective vaccine for the infectious disease that infects 350m to 500m people world-wide and kills over 1m people each year.

The scientists' experimental approach involved exposing two groups of healthy human subjects to mosquitoes once a month over a three-month period. One group was exposed to mosquitoes infected with the malaria parasite, P. falciparum (vaccine group), and the other group to uninfected mosquitoes (control group). During the period of exposure, the human subjects were administered with chloroquine, an anti-malaria drug that prevented P. falciparum from multiplying in the blood. Eight weeks after the last round of immunisation and four weeks after the discontinuation of chloroquine administration, the subjects from both groups were re-exposed to infected mosquitoes and tested for protection against P. falciparum. The scientists found that all the human subjects in the vaccine group had acquired complete protection against the parasite while the subjects in the control group who did not receive immunisation developed parasitemia.

This unique method of immunisation allowed the human immune system to direct its response to eliminating the P. falciparum parasite at the earlier, liver stage of its life cycle, as chloroquine would kill it at the later blood stage. The method used malaria parasites that were whole and intact to induce an immune response as opposed to other methods that included the use of genetically inactivated parasites or parasites that had been weakened by radiation to induce anti-malaria immunity. The experimental results demonstrated a significant improvement over other experimental malaria vaccines currently used in clinical trials that could induce up to only 50 per cent protection in humans.

Professor Renia, principal investigator at SIgN, who had played a pivotal role in this project by conceptualising the experimental protocol, as well as designing and conducting the follow-up experiments, said, "It is not practical to apply the experimental method used in our study as a means of vaccination. But, this method of immunisation could be applied successfully to similar investigations to find biological markers which would indicate the extent of protection against malaria. It would thus advance the currently limited knowledge of what constitutes protective anti-malaria immunity in humans."

Using their novel approach, the scientists examined and gained important insight into the protective anti-malaria immune response in humans, which was difficult to acquire, whether through previous exposure or vaccination. By studying the antibodies, biological substances and cells present in the human subjects from the time of pre- to post-immunisation, the scientists identified a specialised group of parasite-specific immune cells which indicated protection against P. falciparum in humans. These cells, known as pluripotent effector memory T cells, were found in the blood samples of subjects who had been immunised and re-exposed to P. falciparum, but were not found in the subjects in the control group. Hence, the specialised cells could serve as a biological indicator to check for malaria protection in humans during the stages of vaccine development.

Associate professor Raymond Lin, senior consultant and head of Microbiology at the Department of Laboratory Medicine, National University Hospital, said, "This is an elegant study which uses nature itself to tell us the answer to some basic questions regarding what can induce protective immunity against malaria. It shows that exposure to whole unmodified malarial parasites can protect against subsequent infection, while minimising adverse events through the use of anti-malarial drugs. This provides hope for future vaccines and offers prospects of alternatives to conventional vaccine approaches. Also, the remarkable experiment studies infection in humans, using real parasites and real mosquitoes yet in a controlled and safe clinical trial setting. Future vaccine researchers will doubtless refer to this paper for guidance. Malaria is a major health threat in this region which Singaporeans are vulnerable to, so having world-class malaria expertise here is important to us."

Professor Paola Castagnoli, scientific director of SIgN, "Prof Renia has made some very significant findings that will contribute to a better understanding of the anti-malaria immune response in humans. His links with important international research centres and hospitals also demonstrate how collaborations that cross national borders can lead to fruitful and meaningful research outcomes. Certainly, such partnerships will help SIgN build up a strong platform in basic human immunology research that will better translate results into medical applications, and advance the search for cures to urgent medical problems."

SIgN, officially inaugurated on 15 January 2008, is a research consortium under A*STAR's Biomedical Research Council. It is aimed at building on the strengths of the existing immunology research groups at A*STAR, as well as expanding and strengthening the immunology research expertise in Singapore.

The Agency for Science, Technology and Research (A*STAR) is the lead agency for fostering world-class scientific research and talent for a vibrant knowledge-based Singapore.