Down-selection of the VAR2CSA DBL1-2 expressed in E. coli as a lead antigen for placental malaria vaccine development
2018
Over 50 million women are exposed to the risk of malaria during pregnancy every year. Malaria during pregnancy is a leading global cause of maternal morbidity and adverse pregnancy outcomes. Adhesion of Plasmodium falciparum-infected erythrocytes to
placentalchondroitin-4-sulfate (CSA) has been linked to the severe disease outcome of
placentalmalaria. Accumulated evidence strongly supports VAR2CSA as the leading
placental
malaria vaccinecandidate. Recombinant proteins encompassing the VAR2CSA high affinity CSA binding site have been generated, and their activity as immunogens that elicit functional (inhibitory) and
cross-reactiveantibodies against CSA-binding parasites assessed. The expression of His-tagged proteins was compared in four different expression systems and their capacity to bind specifically to CSA was analyzed. CHO cells and E. coli
SHufflecells were the two expression systems able to express some of the recombinant proteins in reasonable amounts. Larger analytical scale production of DBL1x-2× (3D7) and DBL3x-4e (FCR3) best expressed in CHO and E. coli
SHufflecells were performed. Purified proteins were administered to rats either alone or adjuvanted with human approved adjuvants. Analysis of the functionality and
cross-reactivityof the induced antibodies allowed us to down-select the DBL1x-2(3D7) expressed in E. coli
SHufflecells as the best antigen to be transitioned to further clinical development in order to protect future pregnant women living in malaria endemic areas against the severe clinical outcomes of
placentalmalaria.
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