Research ArticleMalaria

Extreme Polymorphism in a Vaccine Antigen and Risk of Clinical Malaria: Implications for Vaccine Development

Science Translational Medicine  14 Oct 2009:
Vol. 1, Issue 2, pp. 2ra5
DOI: 10.1126/scitranslmed.3000257

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Editor's Summary

From the point of view of the parasite, malaria is a successful disease. Transmitted by the bite of infected mosquitoes, malaria sickens about 400 million people a year. Although drugs, insecticides, and bed nets can help, a vaccine would be the most effective way to fight malaria. But the malaria parasite is coated with ever-changing proteins, and it has proven difficult to develop an effective vaccine against these constantly moving targets. By examining the natural immune response to malaria infection in children from Mali, West Africa, Takala et al. have identified antibody targets in the parasite that can best protect children from infection, a boon in designing a vaccine to combat this quick-change artist.

Vaccines against the malaria parasite, Plasmodium falciparum, are directed against proteins on its surface in order to prevent these proteins from initiating the invasion of host cells by the parasite. The main target protein for vaccines currently in development is the highly variable apical membrane antigen–1 (AMA-1). For 3 years, the authors of this study collected P. falciparum organisms that naturally infected 100 children, ages 3 months to 20 years, in a remote rural town. Because each child was repeatedly infected, the authors could determine which characteristics of the infecting parasite determined whether the child was protected from subsequent illness. Sequencing of the parasites’ AMA-1 genes revealed a startling amount of diversity; ~500 separate infections exhibited 214 unique combinations of altered nucleotides. The overall number of resulting amino acid changes in the AMA-1 protein from one infection to another determined whether the child would succumb to sickness with the second infection. That is, the child’s natural immunity from the first infection could only protect against illness in a subsequent infection if AMA-1 from the second infecting parasite was similar to that of the first.

This seems like bad news for malaria vaccine development, but additional data suggest a new approach. The authors’ analysis points to a particular region of AMA-1 (domain I c1L) that is highly variable and is responsible for much of the parasite’s ability to escape control by the human immune system. Thus, a vaccine that elicits protective antibodies to the most common variations of this region might be effective. Understanding how natural immunity to P. falciparum can (and cannot) protect against malaria will help to harness our own immune systems for protection against this serious disease.


  • * Present address: University of Maryland Dental School, Baltimore, MD 21201, USA.