Erythrocyte invasion in malaria: from molecular mechanisms to rational vaccines

Plasmodium parasites, which cause malaria, invade and remodel our red blood cells, creating niches in which they replicate. If erythrocyte invasion is blocked during the blood stage of infection, malaria can be prevented. Indeed, a vaccine that targets a component of the erythrocyte invasion machinery has recently shown efficacy against malaria. Erythrocyte invasion occurs through a sequence of temporally organized molecular processes, such as bridging of the erythrocyte and parasite membranes during invasion by the Plasmodium falciparum PCRCR complex. Structural investigations of human antibodies that target invasion machinery, induced by vaccination or natural infection, have revealed neutralizing epitopes and uncovered mechanisms by which antibodies can potentiate the activity of other antibodies. Using rational, structure-guided protein design, these insights are being leveraged to develop targeted vaccine components, with the first rationally designed blood-stage malaria vaccine immunogen now entering clinical trials.