19th November 2013
by Madushi Wanaguru
Despite numerous efforts over the years, the quest for a malaria vaccine has been met only with modest success. Even the most advanced vaccine candidate to date, RTS,S, conferred only 30 to 50 per cent protection from severe malaria in recent Phase III trials.
The problem may be that the candidate vaccines tested in clinical trials so far (including RTS,S) have targeted only one life-stage of the malaria parasite.
The life cycle of Plasmodium, the parasite that causes Malaria, is a complex one, with different surface proteins or antigens being expressed at different stages. A more effective therapeutic approach may be to combine selected antigens from multiple life-stages in a single vaccine.
Antigens from the blood-stage of the parasite would be important constituents of such a vaccine; not only is this stage responsible for all the clinical symptoms of malaria, it is also directly exposed to the host immune system.
One potential candidate for a blood-stage vaccine is Plasmodium falciparum EBA175, a protein found at the stage when the parasite attempts to invade red blood cells. It was identified to interact with Glycophorin A (GYPA), a protein on the surface of red blood cells, almost three decades ago. This interaction appears to be important as antibodies that target EBA175 inhibit red blood cell entry by P. falciparum.
Plasmodium proteins are notoriously difficult to study in the lab and much of the research into the interaction between EBA175 and GYPA has been done with a sub-fragment of the EBA175 extracellular domain, called Region II (RII) that contains the sequences essential for binding to GYPA. Using a mammalian expression system optimised in our lab, we were recently able to produce the extracellular domain of EBA175 in its full-length form (more than twice the size of RII on its own) as a soluble protein.
We observed that the binding of this full-length EBA175 to GYPA is significantly stronger than that of the sub fragment, RII, suggesting that the extracellular regions of EBA175 outside of RII also play some role in the interaction. We next compared the ability of polyclonal sera raised against the full-length and RII ectodomain forms of EBA175 to block red blood cell invasion by P. falciparum and saw that antibodies targeted to regions other than RII help to inhibit the parasite’s ability to invade.
The data from our study therefore supports the inclusion of regions outside of RII in a future EBA175-based vaccine. By attacking a number of different regions at once, we may stand a better chance of tackling P. falciparum and developing the reliable vaccine that is so crucially needed.
Madushi was a PhD student at the Wellcome Trust Sanger Institute. She worked under the supervision of Gavin Wright and Julian Rayner on the red blood cell invasion pathways of Plasmodium falciparum.
- Wanaguru M K, Crosnier C, Johnson S, Rayner J C, Wright G J (2013) A biochemical analysis of the Plasmodium falciparum Ethrocyte Binding Antigen-175 (EBA175) – Glycophorin-A interaction: implications for vaccine design. The Journal of Biological Chemistry.