Antibodies to PfSEA-1 Block Parasite Egress from RBCs and Protect Against Malaria Infection
Hundreds of millions of people worldwide are infected with the malaria parasite. Of the five species of Plasmodium that infect humans, P. falciparum is the most deadly. Annually, malaria is responsible for up to one million deaths, the majority of which are young children. Despite this, no vaccines currently exist targeted specifically to children. Of great concern is the fact that of the majority of vaccine candidates are based upon only four antigens. Therefore, there is a great need for novel antigen targets. Raj et al (2014) aimed to use information derived from individuals in areas where P. falciparum is endemic to identify a novel malarial antigen.
Using plasma from 2-year-olds they identified three antigens specifically targeted by children resistant to the parasite. One of these, Plasmodium falciparum schizont egress antigen-1 (PfSEA-1), appeared to be essential for blood stage replication. Using an ELISA the authors found that plasma from resistant individuals showed a 4.4 fold greater recognition of PfSEA-1 than plasma derived from susceptible individuals. When parasites were treated in vitro with IgG raised against recombinant PfSEA-1, or with anti-PfSEA-1 derived from human serum, their growth was significantly reduced compared to untreated controls.
To identify where PfSEA-1 is acting the authors used immunofluorescence microscopy and immunogold transmission electron microscopy. PfSEA-1 appeared to localise to the membranes of late schizont infected red blood cells. This localisation pattern combined with its requirement for blood stage development suggested that PfSEA-1 may be involved in egress of the schizonts. Indeed, immunodepletion of PfSEA-1 in vitro resulted in a significant reduction in parasite egress, demonstrating a crucial role for this protein in the parasite life cycle.
The authors then looked to determine the protective potential of vaccination with SEA-1. Mice were vaccinated with recombinant SEA-1 from P. berghei as this strain causes extreme lethality in mice. Three different strains of mice were used and all showed reduced parasite content in the blood compared with controls. Furthermore, vaccination resulted in a ~2 fold increase in survival. Therefore, SEA-1 presents a promising target for the development of vaccines. The authors support this by analysing IgG levels of resistant and susceptible individuals in two human populations. Expression of anti-PfSEA-1 IgG was able to predict resistance to malaria with individuals showing significantly reduced parasite density. This is particularly important as current vaccine candidates such as MSP-3 could not predict resistance.
To conclude, Raj et al (2014) have identified, and begun to characterise, a novel candidate for vaccines against the deadliest form of malaria. PfSEA-1 plays a crucial role in parasite egress with its depletion disrupting the parasite lifecycle. Vaccination of mice with recombinant SEA-1 improves survival and expression of anti-PfSEA-1 IgG predicts resistance in humans. This paper demonstrates the power of combining field and lab based research and provides a paradigm for identifying novel target antigens for vaccines not only against malaria but against all infectious diseases.
Raj et al, (2014) Science, 344, 871-877
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