Title: Identifying naturally occurring antibodies in women resistant to placental malaria to guide future therapeutic development
Funder: The Academy of Medical Sciences

Abstract: Aim: To isolate at least 30 human monoclonal antibodies (hu-mAbs) specific to the VAR2CSA ectodomain from women living in Plasmodium falciparum (Pf) high transmission areas and evaluate their functional potency in-vitro. Objective: Characterise naturally occurring, functional antibodies to VAR2CSA to inform design of a vaccine or therapeutic agent to protect against placental malaria (PM). PM is a serious complication of Pf infection with a severe impact on maternal and infant heath. Pathology results from placental sequestration of infected erythrocytes (IE) via binding of the antigen VAR2CSA, expressed on the surface of IE, with placental chondroitin sulfate A (CSA). Women develop naturally acquired immunity to PM with increasing parity, mediated by antibodies against VAR2CSA. To date, vaccine development has focused on generating antibody responses to single domains of VAR2CSA, however, recent work suggests CSA binding is reliant on formation of a single conformational pocket involving multiple domains. I propose to generate hu-mAbs from memory B cells collected from multiparous women living in areas of high Pf endemicity. These different antibody clones are likely to recognise a range of multi-domain binding epitopes presented in natural infection. After screening these antibodies for functional efficacy using an in-vitro assay of antibody-mediated inhibition of binding of IE to CSA, I will characterize the most potent to understand association between domain binding sites, variable region sequences and biophysical measurements and potency. This work will inform rational design of next-generation VAR2CSA vaccines for PM and may lead to the development of a therapeutic mAb.

Lay abstract: Plasmodium falciparum (Pf) is one of the five Plasmodium species to cause human malaria. While most serious cases of malaria are in children under the age of five, women who become infected with Pf while pregnant can become seriously unwell and have babies who are stillborn, delivered early or underweight. Women are most at risk of these problems during their first pregnancy, due to build-up of parasite-infected red blood cells in the placenta. With each pregnancy the risk of problems from placental infection reduces as women develop antibodies that prevent Pf parasites building up in the placenta. These protective antibodies are targeted against the parasite protein; VAR2CSA and increase with each pregnancy. If we understood how these antibodies work then we could design a vaccine to protect women from Pf disease in pregnancy. It is possible to take a blood sample from an individual, pull out the antibody producing cells and use these to make the antibodies in the laboratory. This project aims to do this with samples from women who live in malaria areas and are likely to have high levels of antibodies that protect against malaria disease in pregnancy. Using laboratory tests, antibodies against VAR2CSA will be chosen and studied in detail to understand how they work. This work will help design an effective vaccine to prevent malaria related poor outcomes in mothers and babies and the best antibody could also be developed as therapeutic drug.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: INFECTION;REPRODUCTIVE HEALTH AND CHILDBIRTH