A broadly cross-reactive i-body to AMA1 potently inhibits blood and liver stages of Plasmodium parasites

Abstract

Broadly cross-reactive anti-malarial vaccines and therapeutic interventions are needed to achieve better outcomes in controlling and, eventually, eradicating malaria. Apical membrane antigen-1 (AMA1) is a structurally and functionally conserved malarial vaccine candidate involved in the tight junction formation with the rhoptry neck protein (RON) complex at the host cell-parasite interface. This interaction is crucial for all Plasmodium parasites to invade human erythrocytes, hepatocytes and mosquito salivary glands effectively. However, extensive surface polymorphisms have induced P. falciparum strain-specific protection which has so far hindered the progression of AMA1-based interventions beyond the first clinical trial. Here, we identified a humanised single-domain (i-body) that recognises a conserved pan-species conformational epitope in AMA1 with low nanomolar affinity and inhibits the binding of the RON2 ligand to AMA1. Structural characterisation indicated that the WD34 i-body epitope engages the centre of the conserved hydrophobic cleft in AMA1, where interacting residues are highly conserved among all Plasmodium species and other apicomplexans. Further, we showed that WD34 inhibits merozoite invasion into RBCs by multiple Plasmodium species and hepatocyte invasion by P. falciparum sporozoites. Our work describes the identification of the first pan-species AMA1 biologic with high multi-lifecycle stage invasion inhibitory activity. This work identifies new tools for species-independent immunoprophylaxis and a possible target for structure-based vaccine development against malaria.