21 December 2012
by Leyla Bustamente
It might take you four minutes to read this report.
In that time, four children will die from the effects of malaria.
The World Health Organisation estimates that there are around 216 million cases of malaria every year, resulting in more than 600,000 deaths, equivalent to more than 2000 fatalities every day. Antimalarial drugs (such as artemisinin-based combination therapies) and insecticides are important weapons in the battle against both the Plasmodium parasite that causes malaria and its mosquito vector.
Although it is difficult to predict what the future might hold, it seems likely that history could repeat itself with the emergence of strong resistance to the main antimalarial drugs and insecticides currently in use, leading to an increase in the numbers of people infected with malaria. We need to develop new drugs, diagnostics, insecticides and a cost-effective vaccine to forestall such a turn and to help to eradicate this disease.
Vaccines are often the most cost-effective ways to combat disease. Historically, they have contributed to a reduction in the spread and burden (and sometimes elimination) of infectious diseases such as smallpox and polio. However, we have, so far, not found an effective vaccine for malaria.
In the work that I am involved in at the Wellcome Trust Sanger Institute, we are interested in discovering how the most virulent species of the Plasmodium parasite in humans(Plasmodium falciparum) is able to gain entry into red blood cells (erythrocytes) – an essential step for both parasite growth and development of malaria symptoms. Last year we identified a protein, basigin, on the surface of human erythrocytes (Crosnier et al. 2011), which is essential for erythrocyte invasion by all strains of P. falciparum tested.
We also discovered that basigin interacts with the PfRH5 protein on the surface of P. falciparum parasites. These findings were an important step in understanding the invasion process and provided a focus for the development of new therapeutics and vaccines.
In developing vaccines that target the steps as the parasite invades the red blood cell, we face the particular challenge of genetic diversity of the Plasmodium parasite. There is a constant battle between the human immune system, which strives to eliminate the parasite, and the ability of the parasite to evade immune detection by continuously changing the sequence and structure of its proteins that are exposed to the human immune system. Such variation makes it difficult to design a vaccine that covers the full range of diversity, and could potentially facilitate the evolution of vaccine-resistant parasite strains.
In our most recent work (Bustamante et al. 2012) we are exploring PfRH5 for its potential as a high priority vaccine candidate for malaria. When we investigated the effect of genetic diversity on the ability of antibodies specific for PfRH5 to inhibit invasion, we found that antibodies raised against the PfRH5 variant of one P. falciparum strain were able to inhibit nine other P. falciparum strains, which between them included all known genetic variants of PfRH5, with no evidence for strain-specific immunity. This finding not only confirmed the importance of the basigin-PfRH5 interaction in establishing infection by the parasite, but underlines the need to include protein-based PfRH5 vaccines in clinical trials.
Bustamante LY, Bartholdson SJ et al. (2012) A full-length recombinant Plasmodium falciparum PfRH5 protein induces inhibitory antibodies that are effective across common PfRH5 genetic variants. Vaccine 31: 373–9
Crosnier C, Bustamante LY, Bartholdson SJ et al. Basigin is a receptor essential for erythrocyte invasion by Plasmodium falciparum. Nature 2011;480: 534–7
Julian Rayner lab: http://www.sanger.ac.uk/research/projects/malariaprogramme-rayner/
Gavin Wright lab: http://www.sanger.ac.uk/research/projects/cellsurfacesignalling/