BIOLOGY OF MALARIA LIVER STAGES - IMPLICATIONS FOR VACCINE DESIGN

The molecular events controlling sporozoite invasion and eso-erythrocy tic (EE) development within hepatocytes are largely not understood, an d EE parasites are probably better defined immunologically than biolog ically. The observation that the Plasmodium falciparum sporozoite anti gen TRAP (thrombospondin-related anonymous protein) contains multiple adhesive domains that recognize endothelial and hepatocyte receptors i ndicates that, like leucocyte passage across capillaries, sporozoite i nvasion probably involves a co-ordinated interaction between sporozoit e and hepatic molecules. The parallel with leucocyte extravasation is strengthened by the finding that TRIP contains a functional, integrin- like, I domain. EE parasites are an important target of immunity elici ted by irradiated sporozoites, and much current effort is focused on d eveloping malaria vaccines targeting EE parasites. Only one EE-specifi c antigen, liver-stage antigen 1 (LSA-1), is known to be expressed dur ing EE development and may contribute to protective immunity elicited by irradiated P. falciparum sporozoites. In a study in Papua New Guine a, resistance to P. falciparum infection correlated with CD8(+) T-cell interferon-gamma responses to an LSA-1 epitope that contains an HLA A ll-restricted sequence. Since All is > 40% frequent in this population it is reasonable to suggest that, as with B53 responses to LSA-1 in T he Gambia, P. falciparum has driven genetic selection of certain HLA h aplotypes, as proposed by Haldane nearly 50 years ago. LSA-1 is thus a n important vaccine candidate, and is being expressed in bacterial and phage vectors.