Immunogenetics and the design of Plasmodium falciparum vaccines for use in malaria-endemic populations.

There are about 500,000,000 cases of clinical malaria of varying severity per year. Some 2 million deaths per year result, almost all of which occur in children living in sub-Saharan Africa and are due to Plasmodium falciparum infection (1). Optimism stemming from the development of vaccines that show some protection against malaria in animals and in malaria-naive humans challenged with laboratory strains of P. falciparum has been dampened by their failure to provide significant, long-lasting protection to individuals living in regions where the disease is endemic. One consequence of the great number of deaths in young children is that malaria has exerted an almost unparalleled selective pressure on humans, leading to the appearance of gene polymorphisms at high frequency, including some for lethal hemoglobinopathies (2). Polymorphic forms of a number of host genes involved in immunity have been associated with protection or susceptibility to malaria. These are likely to predispose populations to unique immune response patterns to vaccines, which may enhance or interfere with their efficacy. Here, we consider some recent findings on host diversity, particularly of gene products involved in immunity. We then discuss the results from recent human vaccine trials, as well as potential strategies to optimize vaccines for use in malaria-endemic areas. Immunity to malaria is quite complex and still not completely understood. The cellular arm of the immune system is considered more important in controlling liver-stage infections, although antibodies contribute to protection; humoral immune mechanisms may be more important in controlling the blood stages. The role of other immune system components is not as well defined, but an involvement in resistance to malaria is often inferred where a particular polymorphism is common in individuals living in malaria-endemic areas. Genes that have come under specific scrutiny include those for components of the innate and acquired immune systems: mannose-binding protein (MBP), inducible nitric oxide synthase (iNOS), Fc receptors, cytokines and cytokine receptors, and the class I and class II MHC molecules.