SBIR-STTR Award

The erythrocytic stage of Plasmodium falciparum kills an estimated 2 million children annually. The parasite invades erythrocytes (RBCs) by attaching to surface receptors, one of which involves sialic acids. The 175 kD P. falciparum protein, erythrocyte binding antigen (BBA-175), binds to RBCs in a sialic acid dependent, receptor-specific fashion. The ability of EBA-175 to bind to RBCs correlates with the ability of these RBCs to be invaded by parasites. The actual sialic acid binding domain of EBA-175 (region 11 has recently been identified. Our specific aim is to determine if antibodies against region 11 of EBA- 175 will block merozoite invasion of RBCs indicating that region Hshould be developed as a malaria vaccine. To accomplish this goal, a plasmid construct with region H of EBA-175 will be expressed by 2 methods in mammalian and prokaryotic cells, and the expressed proteins assessed for their capacity to produce functionally active antibodies. The short term goals of this proposal are 1) to determine if region 11 can induce functional antibodies, and 2) to determine which expression method induces the most functionally active antibodies. The long term goal is to assess the safety, immunogenicity, and protective efficacy of the best immunogen first in Aotus monkeys, and then in humans.Awardee's statement of the potential commercial applications of the research:There are 100-300 million new cases of malaria and 1-2 million deaths caused by malaria annually (WHO, 1990). Every Year 7 million Americans travel to areas of the world where malaria is transmitted, and there are 1000 reported imported cases of malaria in the US each year (Hoffman, 1992). Furthermore, in the 20th century when engaged in malarious areas, the U.S. military has lost more man days to malaria than to bullets (Beadle and Hoffman, 1993). A vaccine against malaria would have enormous domestic and international commercial value.National Institute of Allergy and Infectious Diseases (NIAID)

The erythrocytic stage of Plasmodium faciparum kills an estimated 2 million children annually. The parasite invades erythrocytes by attaching to surface receptors, one of which is sialic acids on glycophorin A. The 175 kD P. falciparum protein, erythrocyte binding antigen (EBA-175), binds to erythrocytes via this sialic acid dependent glycophorin A receptor interaction. The actual receptor binding domain of EBA-175 is region II, ( amino acids 145-760). The specific aim of the Phase I proposal was to prove the principle that antibodies against region II of EBA-175 block merozoite invasion of erythrocytes, indicating that region II should be develop as a malaria vaccine. To accomplish this goal we induced antibodies to region II of EBA-175 in mice by immunizing with region II DNA vaccine and showed that antibodies raised against region II inhibit the binding of native EBA-175 to erythrocytes and inhibit the invasion of merozoites into erythrocytes. In Phase II we will also produce DNA vaccines based on the peptide 4 region of EBA-175, a region which had been shown to induce antibodies with inhibitory activity. We will then assess the capacity of EBA reion II and peptide 4 DNA vaccines along and in combination to induce inhibitory antibodies and protection in Aotus monkeys, and identify an EBA-175 DNA vaccine to be taken into clinical trials in Phase III.Proposed Commercial Application:There are an estimated 30-500 million new cases of malaria and 1.5-2.7 million deaths caused by malaria annually (World Health Organization, 1995). Every year tens of million North Americans and Europeans travel to areas of the world where malaria is transmitted, and thousands of these travelers acquire malaria each year (Hoffman, 1992). Furthermore, during the 20th century when engaged in areas of the world where malaria is transmitted, the U.S. military has generally lost more man days to malaria then to bullets (Beadle and Hoffman, 1993). A vaccine against malaria would have enormous international and domestic commercial value.