Pregnancy malaria (PM) affects estimated 50 million women worldwide and contributes to 200,000 infant deaths annually. Caused by sequestration of chondroitin sulfate A (CSA) binding Plasmodium falciparum parasites in placenta, PM increases risks of maternal anemia, stillbirth, spontaneous abortion, low birth weight, neonatal death, and preeclampsia. Previous ex vivo experiments have shown the mechanism of CSA binding in placenta can be inhibited by treating parasites with sera from multigravida women of malaria endemic area or animals immunized with antigens critical for parasite adhesion. During the past fiscal year, LMIV scientists have accomplished the following: 1. Continued development of a mouse model of pregnancy malaria. Using a panel of P. chabaudi isolates (heterologous strains AS, CB and ER have been under study), we have developed a mouse model of both malaria recrudescence and malaria reinfection during pregnancy in C57BL6 mice, and have found that malaria severity and poor outcomes are related to production of inflammatory cytokines such as TNFa and MCP1, and the anti-inflammatory cytokine IL10. Over the past year, we have observed that malaria in the mother modulates the severity of malaria in her offspring when inoculated with parasites during infancy. The results are similar to our observation in human studies that maternal malaria increases the risk of severe malaria in offspring. 2. We described in previous reports the first ever non-human primate model of placental malaria, by showing the sequestration of P. falciparum parasites in the placenta of pregnant Aotus monkeys, and showing the acquisition of broadly neutralizing antibodies in some monkeys after PM experience-- all similar to observations in humans. Over the past year we have been preparing for a scaled up assessment of our Aotus model, in collaboration with the European vaccine Initiative. Animals have been procured that will allow us to demonstrate the protective efficacy of 1) broadly neutralizing IgG passively transferred to the Aotus to prevent placental sequestration; 2) immunization with the leading vaccine candidates from Europe and NIH intended to prevent placental parasite sequestration. 3. VAR2CSA has been the primary focus of PMV vaccine development for the malaria research community. In previous reports, we described PfCSA-L as a novel invariant surface antigen that associates with VAR2CSA on the surface knobs of Pf-IE,mediates binding to placental CSA, and induces anti-adhesion antibodies. As a highly conserved protein of small size (25 kDa), PfCSA-L appears to be a valuable target for placental malaria vaccine development. Over the past year, we have developed methods to prepare complexed forms of PfCSA-L and VAR2CSA so that we can study the protein complex as an immunogen. Our hypothesis is that the complex provides novel epitopes that are targets of broadly neutralizing antibodies. 4. Prepared two VAR2CSA immunogens (which incorporate the ID1-DBL2-ID2a domains) that induce antibodies in rodents which are able to inhibit binding of 33-56% of fresh field isolates in the initial year of testing. These immunogens constitute our leading candidates for a PM vaccine.
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