A broadly neutralising PvDBP-targeting antibody to block vivax malaria

Tracking down a broadly-neutralising antibody to stop Plasmodium vivax

Plasmodium vivax causes one of the two most widespread forms of human malaria. To cause disease, and to be transmitted, the parasite must get inside immature human red blood cells. Essential in this process is PvDBP, a molecule which interacts with the DARC receptor on the blood cell surface. But PvDBP is variable and polymorphic. Can we find antibodies which block all of the variants of PvDBP?

pvdbp

Vaccination of a group of volunteers in Oxford with a PvDBP-based vaccine, provided Tom Rawlinson from Simon Draper’s group with the opportunity to identify and characterise a set of human antibodies which target PvDBP. 

Tom then used three different assays to assess the efficacy of these antibodies. As Plasmodium vivax cannot currently be grown in culture in a laboratory, Tom worked in Thailand to test the ability of his antibodies to block blood cell invasion by parasites taken straight from malaria patients. He also studied the ability of the antibodies to prevent PvDBP from binding to DARC in a protein assay. Finally, he used a trick developed by Rob Moon’s group, in which a parasite which can be cultured, Plasmodium knowlesi, was modified to require PvDBP to grow. Combining the results of these three assays identified DB9, an antibody with broadly inhibitory activity.

Next, Natalie Barber was able to crystallise DB9 bound to the region of PvDBP which it targets. This revealed that DB9 binds to a non-polymorphic site distant from the region of PvDBP thought to mediate binding to DARC. However, modelling suggests that it may work by preventing PvDBP from getting close enough to DARC to allow it to bind.

The discovery of DB9 therefore identifies a novel site to target with antibodies and informs the design of future vaccine components against vivax malaria. 

Rawlinson, T.A., Barber, N.M., Mohring, F., Cho, J.S., Kosaisavee, V., Gérard, S.F., Alanine, D.G.W., Labbé, G.M., Elias. S.C., Silk, S.E., Quinkert, D., Jin, J., Marshall, J.M., Payne, R.O., Minassian, A.M., Russell, B., Rénia, K., Nosten. F.H., Moon, R.W., Higgins, M.K.* and Draper, S.J.* (2019) Structural basis for inhibition of Plasmodium vivax invasion by a broadly neutralising vaccine-induced human antibody. Nature Microbiology 4 1497-1507 (*joint corresponding)