Pregnancy Malaria Vaccine development

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications & trials

Abstract

Placental malaria (PM) is a major public health problem associated with severe maternal anemia, preeclampsia, pregnancy loss, low birthweight delivery and infant mortality. PM is caused by sequestration in the placenta of parasites that bind the receptor chondroitin sulfate A (CSA). Previous ex vivo experiments have shown that parasite binding to CSA can be inhibited by antibodies from multigravida women who acquired specific immunity to CSA-binding parasites, or by antibodies from animals immunized with antigens that mediate parasite binding to CSA. From our publication this year, we report the following advances in FY2021: 1. Renn JP, Doritchamou JYA, Duffy PE. Expression of large full-length PfEMP1 proteins in HEK293 cells. 2021. Methods in Molecular Biology. In press. Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) is a family of proteins expressed on the surface of red blood cells infected by Plasmodium falciparum. PfEMP1 proteins play a vital role in parasite virulence, and thus are important vaccine candidates to prevent severe disease. VAR2CSA is one specific PfEMP1 essential for pregnancy malaria pathogenesis, and the primary target in pregnancy malaria vaccine development. However, similar to other PfEMP1 proteins, expression of recombinant full-length VAR2CSA is difficult due to its large size, multidomain architecture and high cysteine content. To date, there has been success using higher ordered expression systems (such as mammalian and insect cells) to generate folded and active VAR2CSA. However, recent improvements with mammalian expression systems including cell lines and promoters have pushed the boundaries of yields. Here, we describe a modified protocol beyond current systems that enhances yields of full-length VAR2CSA that can generate higher quantities of material for protein structural and functional characterization. 2. Ma R, Lian T, Huang R, Renn JP, Petersen JD, Zimmerberg J, Duffy PE, Tolia NH: Structural basis for placental malaria mediated by Plasmodium falciparum VAR2CSA. Nat Microbiol 2021, 6:380-391. LMIV scientists made a major technical advance that now support these expression of full-length VAR2CSA ectodomains in mammalian cells. We exploited this advance to conduct cryo-electron microscopy structures of the full-length ectodomain of VAR2CSA in complex with CSA, in studies led by the Tolia group. This work provides paths for improving the design of VAR2CSA-based placental malaria vaccines.