Structure-guided design of aPlasmodium vivaxDuffy binding protein-based vaccine immunogen

Abstract

AbstractPlasmodium vivaxremains one of the major causative agents of human malaria and a vaccine is urgently required. It is an obligate intracellular parasites and replication within red blood cells is essential for development of disease and for transmission. The interaction between PvDBP on the parasite surface and the DARC receptor on human reticulocytes is essential for aPlasmodium vivaxblood stage infection. Human vaccination with the RII region of PvDBP slowed parasite replication, showing that PvDBP is a promising vaccine candidate. However, it did not induce sterile protection, and further development is required to generate a vaccine which protects from clinical malaria. In this study, we develop a vaccine immunogen containing a region of PvDBP-RII, known as subdomain 3, which contains the epitope for a broadly-reactive growth-inhibitory antibody, DB9. We used structure-guided approaches to resurface subdomain 3 such that it folds as an isolated molecule. We show that this engineered subdomain 3 is more stable and more easily produced than PvDBP-RII and induces a more effective growth-inhibitory antibody response. We therefore present an improved PvDBP-based immunogen for use in blood stage vaccines to prevent malaria due toPlasmodium vivax.One sentence summaryStructure-guided design leads to a more effective Duffy-binding protein-based vaccine immunogen to preventPlasmodium vivax.