Recombinant VAR2CSA proteins as vaccine candidates for placental malaria
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Placental malaria is caused by P. falciparum infected Erythrocytes (PE) that bind to the placental receptor Chondroitin Sulphate A (CSA) and sequester in the placenta1, where they cause disease and death for the mother and her off-spring. Every year, more than 100 million pregnant women are threatened by placental malaria, which causes the death of 80,000 - 200,000 children2. Currently for placental malaria the only preventive strategies to improve maternal and fetal outcomes include intermittent preventive treatment (IPT) and insecticide-treated bed nets. However, resistance to drugs used for IPT by the parasite and waning efficacy of the bed nets due to insecticide resistance in the vector represent major threats. This problem has long been neglected, and no vaccine preventing placental malaria is available.
The European Vaccine Initiative (EVI) has been instrumental in the mobilisation of €16 million for the development of vaccines against placental malaria, through the German Federal Ministry of Education and Research (BMBF) through Kreditanstalt für Wiederaufbau (KfW) funded projects PRIMALVAC and PAMCPH (as part of the EDCTP2 programme supported by the European Union) as well as the European Commission (EC) Framework Programme 7 funded project PlacMalVac. Dr Odile Leroy: “With these three projects EVI has become the leading Product Development Partnership to advance the development of vaccines against pregnancy-associated malaria. These projects offer hope for reducing the burden of severe malaria in pregnant women and improving the health of mothers and new-borns”. Apart from the funding provided by the BMBF and the EC, the three projects receive major co-funding from Irish Aid (through EVI), the Institut national de la santé et de la recherche médicale (Inserm) and the Institut National de la Transfusion Sanguine (INTS), and additional contributions from the Universities of Copenhagen and Benin, the Danish National Advanced Technology, the Institut de Recherche pour le Développement (IRD), and by ExpreS2ion Biotechnologies, respectively. Moreover, in order to strengthen the network between the main groups working on a placental malaria vaccine, EVI has set up a collaboration with the United States – National Institutes of Health (NIH).
The three placental malaria projects focus on the distinct form of the parasite that infects the placenta, causing disease and death in mothers and infants. Evidence strongly supports VAR2CSA, a member of the PfEMP1 adhesins encoded by the var gene family, as the leading candidate for a placental malaria vaccine3,4,5. Indeed, VAR2CSA is preferentially expressed by placental parasites and the protein binds to CSA6. Women acquire antibodies against VAR2CSA expressed by placental parasites over successive pregnancies, as they become resistant to pregnancy malaria7. These data provide a rational basis for accelerating vaccine development aimed at blocking the adhesion of CSA-binding parasites to the placenta.
The target product profile of placental malaria vaccines notably differs from the currently developed malaria vaccine. Placental malaria vaccines target young adolescent girls before childbearing age, and the vaccination could be associated to other vaccines targeting either prevention of rubella or prevention of uterine cervical cancer by Human papilloma virus vaccine. Depending on the other malaria vaccine available on the market, a placental malaria vaccine could potentially be associated with a booster dose of a regular malaria vaccine in adolescent girls.
The PRIMALVAC project, whose vaccine inventor is Dr Benoit Gamain (Inserm, France), includes the transition of a VAR2CSA candidate antigen that best meet strict immunogenicity criteria to preclinical and clinical development. The PAMCPH project focusses on the production of another recombinant VAR2CSA vaccine candidate discovered by Prof Ali Salanti and Prof Thor Theander (University of Copenhagen, Denmark) under current Good Manufacturing Practice (cGMP). This vaccine candidate will be used in the phase I clinical trial supported by the PlacMalVac project, in collaboration with the five project partners (University of Copenhagen, IRD, Expres2ion Biotechnologies, EVI, Université d’Abomey-Calavi, and Eberhard Karls University Tuebingen). The main common objective of these projects is to obtain proof of concept that a VAR2CSA based vaccine inducing long lasting or rapidly boosted cross reactive and inhibitory antibodies can be designed for human use.
African woman with her child (photo kindly provided by Roll Back Malaria)
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- Fried M, Duffy PE. Adherence of Plasmodium falciparum to chondroitin sulfate A in the human placenta. Science. 1996 Jun 7;272(5267):1502-4.
- Hartman TK et al., The impact of maternal malaria on new-borns. Annals of Tropical Paediatrics. 2010;30:271-282
- Baruch DI, Pasloske BL, Singh HB, Bi X, Ma XC, Feldman M, et al. Cloning the P. falciparum gene encoding PfEMP1, a malarial variant antigen and adherence receptor on the surface of parasitized human erythrocytes. Cell. 1995 Jul 14;82(1):77-87
- Su XZ, Heatwole VM, Wertheimer SP, Guinet F, Herrfeldt JA, Peterson DS, et al. The large diverse gene family var encodes proteins involved in cytoadherence and antigenic variation of Plasmodium falciparum-infected erythrocytes. Cell. 1995 Jul 14;82(1):89-100
- Smith JD, Chitnis CE, Craig AG, Roberts DJ, Hudson-Taylor DE, Peterson DS, et al. Switches in expression of Plasmodium falciparum var genes correlate with changes in antigenic and cytoadherent phenotypes of infected erythrocytes. Cell. 1995 Jul 14;82(1):101-10.
- Salanti A, Staalsoe T, Lavstsen T, Jensen AT, Sowa MP, Arnot DE, et al. Selective upregulation of a single distinctly structured var gene in chondroitin sulphate A-adhering Plasmodium falciparum involved in pregnancy-associated malaria. Mol Microbiol. 2003 Jul;49(1):179-91.
- Fried M, Nosten F, Brockman A, Brabin BJ, Duffy PE. Maternal antibodies block malaria. Nature. 1998 Oct 29;395(6705):851-2