Structure of the malaria vaccine candidate antigen CyRPA and its complex with a parasite invasion inhibitory antibody

Abstract

Invasion of erythrocytes by Plasmodial merozoites is a composite process involving the interplay of several proteins. Among them, the Plasmodium falciparum Cysteine-Rich Protective Antigen (PfCyRPA) is a crucial component of a ternary complex, including Reticulocyte binding-like Homologous protein 5 (PfRH5) and the RH5-interacting protein (PfRipr), essential for erythrocyte invasion. Here, we present the crystal structures of PfCyRPA and its complex with the antigen-binding fragment of a parasite growth inhibitory antibody. PfCyRPA adopts a 6-bladed β-propeller structure with similarity to the classic sialidase fold, but it has no sialidase activity and fulfills a purely non-enzymatic function. Characterization of the epitope recognized by protective antibodies may facilitate design of peptidomimetics to focus vaccine responses on protective epitopes. Both in vitro and in vivo anti-PfCyRPA and anti-PfRH5 antibodies showed more potent parasite growth inhibitory activity in combination than on their own, supporting a combined delivery of PfCyRPA and PfRH5 in vaccines.

DOI: http://dx.doi.org/10.7554/eLife.20383.001

eLife digest

Malaria is one of the deadliest infectious diseases worldwide, killing over 400,000 people a year. About 200 million people are infected every year, placing a huge social and medical burden especially on developing countries. Microscopic parasites known as Plasmodium are responsible for causing this disease. Plasmodium parasites have a complex life cycle involving both mosquito and mammal hosts. This includes a stage where the parasites infect the mammal’s red blood cells, which causes the symptoms of the disease. In 2012, a team of researchers discovered that a protein called CyRPA forms a group (or ‘complex’) with several other proteins to allow the parasites to enter red blood cells.

Developing a vaccine is one of the most promising approaches to prevent malaria. Vaccines help the body to recognise and fight an invading microbe by triggering an immune response that results in the production of proteins called antibodies, which can bind to specific molecules on the surface of the microbe. If the microbe later enters the body, these antibodies can be produced quickly to eliminate the microbe before it causes disease. However, efforts to develop a highly effective vaccine against malaria have so far been unsuccessful.

Favuzza et al. – including some of the researchers involved in the 2012 work – used a technique called X-ray crystallography to investigate the three-dimensional structure of the CyRPA protein. The experiments show that an antibody is able to bind to a region of CyRPA – a designated ‘protective epitope’ – that is similar in the CyRPA proteins of all Plasmodium falciparum strains. These antibodies can prevent the parasite from entering the red blood cells, and vaccines containing CyRPA may therefore be effective at protecting individuals from malaria. The findings of Favuzza et al. also suggest that using CyRPA in combination with another protein in the complex called RH5 could make the vaccine more powerful as it would make it harder for the parasite to become resistant.

The next step following on from this work is to design a vaccine containing protective CyRPA epitopes that triggers an immune response in mammals that is strong enough to reduce the numbers of parasites in the blood. A future challenge will be to develop a vaccine that combines several proteins involved in different stages of the parasite’s life cycle to provide full protection against malaria.

DOI: http://dx.doi.org/10.7554/eLife.20383.002