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. LMIV is committed to develop pregnancy malaria vaccines that will protect women through production of anti-adhesion antibodies. During the past fiscal year, LMIV scientists have accomplished the following: 1. Launched several studies to develop new animal models for better understanding of PM pathogenesis and immunity. Thus far, we have established that pregnancy can cause recrudescence of malaria in rodents with chronic parasitemia, which is similar to the epidemiology observed in pregnant women. We have also established a colony of African thicket rats obtained from Congo, which are the natural hosts for the rodent malaria parasite species, and we plan to examine pregnancy malaria patterns in these animals. 2. Developed, characterized, and raised anti-adhesion antibodies for different variants of antigens (VAR2CSA and PfCSA-L) critical for CSA binding, and demonstrated inhibition efficacy of the products with CSA binding parasites. Our data indicate that E. coli expressed forms of our leading antigens can induce functional anti-adhesion antibodies with activity against heterologous isolates, including fresh placental parasites 3. Established capabilities and processes to identify novel antigens involved in molecular pathogenesis of PM. We have now confirmed that the conserved antigen PfCSA-L, which we identified earlier through a microarray screen of pregnancy malaria parasites, binds with high affinity to the variant surface antigen VAR2CSA. These data suggest that our leading candidate antigens for a pregnancy malaria vaccine may form a complex on the surface of the infected red cell. We are exploring whether vaccinating with the complex of these 2 proteins may be superior as an immunogen for eliciting functional antibodies that block parasite binding in the placenta.

Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2012
Total Cost
$682,580
Indirect Cost
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State
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Harrington, Whitney E; Fried, Michal; Duffy, Patrick E (2016) Defending the Use of Sulfadoxine-Pyrimethamine for Intermittent Preventive Treatment for Malaria in Pregnancy: A Short-Sighted Strategy. J Infect Dis 213:496-7
Gullingsrud, Justin; Milman, Neta; Saveria, Tracy et al. (2015) High-throughput screening platform identifies small molecules that prevent sequestration of Plasmodium falciparum-infected erythrocytes. J Infect Dis 211:1134-43
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Kabyemela, Edward; Gonçalves, Bronner P; Prevots, D Rebecca et al. (2013) Cytokine profiles at birth predict malaria severity during infancy. PLoS One 8:e77214
Fried, Michal; Avril, Marion; Chaturvedi, Richa et al. (2013) Multilaboratory approach to preclinical evaluation of vaccine immunogens for placental malaria. Infect Immun 81:487-95
Obiakor, Harold; Avril, Marion; Macdonald, Nicholas J et al. (2013) Identification of VAR2CSA domain-specific inhibitory antibodies of the Plasmodium falciparum erythrocyte membrane protein 1 using a novel flow cytometry assay. Clin Vaccine Immunol 20:433-42
Saveria, Tracy; Oleinikov, Andrew V; Wiliamson, Kathryn et al. (2013) Antibodies to Escherichia coli-expressed C-terminal domains of Plasmodium falciparum variant surface antigen 2-chondroitin sulfate A (VAR2CSA) inhibit binding of CSA-adherent parasites to placental tissue. Infect Immun 81:1031-9
Harrington, Whitney; McGready, Rose; Muehlenbachs, Atis et al. (2012) Intermittent preventive treatment in pregnancy with sulfadoxine-pyrimethamine: the times they are a-changin'. Clin Infect Dis 55:1025-6; author reply 1026-7

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