The Plasmodium falciparum erythrocyte membrane protein 1 antigens that are inserted onto the surface of P. falciparum infected erythrocytes play a key role both in the pathology of severe malaria and as targets of naturally acquired immunity. They might be considered unlikely vaccine targets because they are extremely diverse. However, several lines of evidence suggest that underneath this molecular diversity there are a restricted set of epitopes which may act as effective targets for a vaccine against severe malaria. Here we review some of the recent developments in this area of research, focusing on work that has assessed the potential of these molecules as possible vaccine targets.

Malaria remains one of the biggest health problems in large parts of the world. In sub-Saharan Africa alone, it is currently estimated that there are more than 150 million clinical cases annually, and that about 2 million people die from the disease every year. The bulk of malaria-related morbidity and mortality in an endemic setting (malaria is regularly found) is concentrated in children below the age of five years, and the increasing resistance to infection and disease with age is conventionally thought to reflect a slow and gradual acquisition of protective immunity. Many recent and comprehensive reviews of malarial immunity exist; rather than attempting to add another, this review summarises some of the recent evidence on how protective immunity is acquired in humans and what precipitates clinical disease, specifically as it relates to populations living in areas where the disease is endemic. It is becoming increasingly clear that naturally acquired protective immunity depends largely on responses directed against highly variable parasite antigens. This implies that a successful blood-stage vaccine against this disease must be able to either induce protective responses against many of these variants, or artificially initiate protective immune responses that do not normally occur following natural exposure to the parasites. Such protective immune responses might either rely on a different immunological mechanism, or be directed against other antigens, other than those seen in naturally acquired protective immunity. It remains to be seen whether it will be possible to induce protective responses such as these by ‘artificially’ immunising humans.

A deterministic mathematical model which predicts the probability of developing a new drug-resistant parasite population within the human host is reported. The model incorporates the host's specific antibody response to PfEMP1, and also investigates the influence of chemotherapy on the probability of developing a viable drug-resistant parasite population within the host. Results indicate that early treatment, and a high antibody threshold coupled with a long lag time between antibody stimulation and activity, are risk factors which increase the likelihood of developing a viable drug-resistant parasite population. High parasite mutation rates and fast PfEMP1 var gene switching are also identified as risk factors. The model output allows the relative importance of the various risk factors as well as the relationships between them to be established, thereby increasing the understanding of the conditions which favour the development of a new drug-resistant parasite population.

A new mathematical model of Plasmodium falciparum asexual parasitaemia is formulated and fitted to 35 malaria therapy cases making a spontaneous recovery after primary inoculation. Observed and simulated case-histories are compared with respect to 9 descriptive statistics. The simulated courses of parasitaemia are more realistic than any previously published. The model uses a discrete time-step of 2 days. Its realistic behaviour was achieved by the following combination of features (i) intra-clonal antigenic variation, (ii) large variations of the variants' baseline growth rate, depending on both variant and case, (iii) innate autoregulation of the asexual parasite density, variable among cases, (iv) acquired variant-specific immunity and (v) acquired variant-transcending immunity, variable among cases. Aspects of the model's internal behaviour, concerning variant dynamics, as well as the respective contributions of the three control mechanisms (iii) – (v), are displayed. Some implications for pathogenesis and control are discussed.

Antibodies against variable antigens expressed on the surface of Plasmodium falciparum-infected erythrocytes are believed to be important for protection against malaria. A target for these antibodies is the P. falciparum erythrocyte membrane protein 1, PfEMP1, which is encoded by around 50 var genes and undergoes clonal variation. Using agglutination and mixed agglutination tests and flow cytometry to analyse the recognition of variant antigens on parasitized erythrocytes by plasma antibodies from individuals living in Daraweesh in eastern Sudan, an area of seasonal and unstable malaria transmission, we show that these antibodies recognize different variant antigens expressed by parasites of different genotype. Comparing the levels and acquisition of antibody to variant antigens in pairs of parasite isolates expressing different variant types, there is a correlation between the acquisition of antibodies to some combinations of variant antigens but not to others. These results indicate that (1) a single infection will induce the production of antibodies recognizing several variants of surface-expressed antigens, (2) the repertoire of variable antigens expressed by different parasites is overlapping and the degree of overlap differs between isolates, and (3) the expression of at least some variant antigens is genetically linked.