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.
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.
| Ambroggio, Xavier; Jiang, Lubin; Aebig, Joan et al. (2013) The epitope of monoclonal antibodies blocking erythrocyte invasion by Plasmodium falciparum map to the dimerization and receptor glycan binding sites of EBA-175. PLoS One 8:e56326 |
| Sim, B Kim Lee; Narum, David L; Chattopadhyay, Rana et al. (2011) Delineation of stage specific expression of Plasmodium falciparum EBA-175 by biologically functional region II monoclonal antibodies. PLoS One 6:e18393 |
