Structure-guided design of a vaccine immunogen against Plasmodium vivax

Some of the most promising vaccine candidates against forms of malaria caused by Plasmodium vivax are based on the Duffy binding protein, PvDBP. Indeed, vaccination of volunteers with a piece of PvDBP, known as PvDBP-RII, reduced the growth rate of parasites upon infection. However, PvDBP-RII is very hard to make and did not lead to clinical prevention against disease. Can we make it better?

We had previously shown that a very effective antibody that prevents Plasmodium vivax from getting inside human blood cells binds to a region of PvDBP-RII called subdomain 3. What would happen if we vaccinate with subdomain 3 instead of PvDBP-RII?

The challenge here is that subdomain 3 is not easily produced in a soluble form. Could we make it better? Analysis of the structure of PvDBP-RII suggested the reason why it might be problematic. Subdomain 3 normally packs against other parts of PvDBP-RII through a hydrophobic patch. When subdomain 3 is removed from PvDBP-RII, this patch will be exposed. Could this be making subdomain 3 unstable?

We therefore re-engineered the hydrophobic patch of subdomain 3 to produce a version that we called interface. We were excited to find that interface expresses in a soluble form in large quantities, that it folds correctly and that it binds to neutralising antibodies. Finally, we tested interface in a pre-clinical malaria model and found that it induced a much larger quantity of inhibitory antibodies than PvDBP-RII.

Therefore, we have used structural insight to design a new and improved form of PvDBP. This can be easily produced in a folded form and is therefore suitable for use in a range of vaccine platforms, from protein-based to mRNA-based vaccines. This immunogen is now ready to enter human clinical trials, where we hope that it will induce much improved protection against Plasmodium vivax.

Barber, N.M.,*, Pholcharee, T.*, Lias, A.M., Quinkert, D., Nugent, J., King, L.D.W., Draper, S.J. and Higgins, M.K. (2024) Structure-guided design of a Plasmodium vivax Duffy binding protein-based vaccine immunogen. BioRXIV doi.org/10.1101/2024.06.23.600241 (*equal contributions)