"An effective malaria vaccine is needed, particularly against P. falciparum as this species causes more human mortality than all other eukaryotic pathogens combined. An understanding of natural selection operating on parasites in local endemic populations can enable understanding of core molecular mechanisms of global relevance. The objectives are to- Advance understanding of alternative pathways of erythrocyte invasion by malaria parasites- Advance understanding of immune evasion by malaria parasites- Identify optimal combinations of parasite proteins as malaria vaccine candidates- Develop the interface between population genomic and functional studies of malaria parasitesThe research programme will take an integrated approach to understanding pathogen adaptation, by designing experiments that are based on analysis at the molecular, functional, and population levels.(i) Population genetic analyses of P. falciparum in sites of contrasting endemicity in West Africa, to finely determine signatures of selection with high-resolution throughout the genome, and help refine hypotheses on mechanisms used by merozoites to invade erythrocytes and evade acquired immune responses.(ii) Experimental culture analysis of merozoite invasion into erythrocytes to identify the receptor-ligand interactions used by different parasite populations ex vivo. Novel receptor knockdown assays on cultured erythrocytes will be employed, and parasite adaptation experiments conducted to identify constraints on the use of alternative invasion pathways(iii) Innovative approaches to select individual parasites and characterise cell tropism, transcript profiles, and genome sequences. This is aimed to validate population level findings and revolutionise approaches to genetics and phenotyping of parasites in the future. Candidate molecule discoveries will be taken forwards to receptor-ligand interaction assays, antibody inhibition and immuno-epidemiological studies."