Development of vaccines against blood-stage P. vivax

Plasmodium vivax is the most geographically widespread of the Plasmodium species causing human malaria. Despite the fact its global socio-economic burden is comparable to that of its deadlier cousin P. falciparum, research into a P. vivax vaccine has been neglected for a long time. An effective vaccine, reducing morbidity and transmission would help eradicate this devastating disease.

During the blood-stage of the life cycle of P. vivax, the parasites invade immature red blood cells - reticulocytes - where they replicate to large numbers and cause the symptoms associated with malaria. Our efforts aim to design vaccines that ultimately prevent the invasion of reticulocytes. In this context, the main candidate antigen for the development of a vaccine against P. vivax is the Duffy-binding protein – PvDBP. Through its interaction with the Duffy antigen receptor for chemokines, DARC/Fy, on the surface of reticulocytes, PvDBP plays an essential role for parasite invasion. Importantly, a human polymorphism that results in “Duffy blood group-negative” red blood cells is associated with natural protection from P. vivax and is widespread across Africa, where this parasite is largely absent. Moreover, in humans, high-titres of naturally acquired antibodies that target PvDBP and inhibit DARC binding are associated with reduced risk of P. vivax infection. Blocking this molecular interaction, with antibodies induced by vaccination, is thus a highly attractive strategy for vaccine development. Remarkably, although this aspect of parasite biology was first reported in 1976, it is only in the last few years, that sufficient momentum has grown to begin clinical testing of candidate vaccines.

PvDBP can be divided into six distinct regions, with the DARC binding site mapped to a ~350 amino acid domain known as Region II – PvDBPII. PvDBPII binds to the sixty-residue N-terminal extracellular domain of DARC. PvDBPII is thus the target antigen that we tested in our first clinical vaccine trials, following preclinical studies that showed how PvDBPII-based vaccines induce inhibitory antibodies that block binding of recombinant PvDBPII to DARC.

One of the key challenges that we face with this research, is the lack of sustained long-term culture of P. vivax in the laboratory, making it difficult to robustly test antibody-inducing vaccines in standardised functional growth inhibition assays, of the type traditionally performed for vaccines targeting P. falciparum. Recently, through a collaboration with Prof Rob Moon at the London School of Hygiene & Tropical Medicine, we have been using a surrogate growth inhibition assay that uses genetically engineered P. knowlesi parasites in which the PkDBP gene has been replaced with that of P. vivax. This important development now means we can far more easily test antibody function against PvDBP in the lab, and assess for in vitro correlates of vaccine-induced protection in our clinical trials.

PvDBP-DARC interaction at the merozoite-reticulocyte interface

For more information:

de Cassan, Simone C., et al. "Preclinical assessment of viral vectored and protein vaccines targeting the Duffy-binding protein region II of Plasmodium vivax." Frontiers in immunology 6 (2015): 348.

Payne, Ruth O., et al. "Human vaccination against Plasmodium vivax Duffy-binding protein induces strain-transcending antibodies." JCI insight 2.12 (2017).

Rawlinson, Thomas A., et al. "Structural basis for inhibition of Plasmodium vivax invasion by a broadly neutralizing vaccine-induced human antibody." Nature microbiology 4.9 (2019): 1497-1507.