Globally, the Plasmodium falciparum parasite is responsible for at least 300 million acute cases of malaria each year, with more than 1 million deaths. Approximately 90 percent of these deaths, the majority in children under 5 years of age, occur in Africa due to infection with Plasmodium falciparum. Morbidity and mortality caused by malaria also has significant direct and indirect costs on the economic development of the endemic countries. It is estimated that malaria accounts for 40 percent of public health expenditures, more than 30 percent of inpatient admissions, and approximately 50 percent of outpatient visits in some African countries. These factors, as well as growing drug resistance of the parasite, widespread resistance of mosquitoes to insecticide, and increased human travel necessitate the need for new approaches to malaria control and eradication. A vaccine that could reduce both mortality and morbidity secondary to Plasmodium falciparum infection would be a valuable resource in the fight against this disease.
Over time, people living in endemic areas develop natural immunity to Plasmodium falciparum as a result of repeated infection. Consequently, children who survive to 7 to 10 years of age rarely succumb to life-threatening disease despite frequent infection. This acquired immunity is mediated in part by blood-stage parasite-specific antibodies. Thus, parasite proteins expressed during the blood-stage have been proposed to be good candidates for inclusion in a vaccine. The purpose of a blood-stage vaccine is to elicit immune responses that either destroy the parasite in the blood stream or inhibit the parasite from infecting red blood cells, thus reducing or preventing complications of the disease.
A number of Plasmodium falciparum merozoite antigens have been identified as promising blood-stage vaccine candidates, including Apical Membrane Antigen 1 (AMA1). The precise role of AMA1 in the parasite is unknown; however, it is critical in the erythrocyte invasion process across divergent Plasmodium species and for blood-stage multiplication of the parasite. Recent analysis of the Plasmodium falciparum proteome detected expression of AMA1 in the sporozoite stage and suggests an additional role for AMA1 during the liver-stage invasion. Therefore, an immune response against AMA1 may have an effect on liver-stage parasites as well as having an impact on blood-stage parasites, thus protecting the host by multiple immune mechanisms. Human and animal anti-AMA1 antibodies inhibit merozoite invasion in vitro and correlate with protection against parasite challenge in animal models. T-cells specific for Plasmodium falciparum AMA1 have also been demonstrated in individuals living in endemic areas.
At least 68 known amino acid polymorphisms of AMA1 have been demonstrated, and animal studies have shown that the polymorphisms in AMA1 are not immunologically silent. The combination of two or more divergent AMA1 sequences within a single vaccine formulation may reduce evasion of the host immune response by some Plasmodium falciparum field isolates.
