Towards an anti-disease malaria vaccine

Abstract

Human infective parasites, such as those that cause malaria, are highly adapted to evade clearance by the immune system. In situations where they must maintain prolonged interactions with molecules of their host, they often use parasite surface protein families. These families are highly diverse to prevent immune recognition, and yet, to promote parasite survival, their members must retain the ability to interact with specific human receptors. One of the best understood of the parasite surface protein families is the PfEMP1 proteins of Plasmodium falciparum. These molecules cause infected erythrocytes to adhere to human receptors found on blood vessel and tissue surfaces. This protects the parasite within from clearance by the spleen and also causes symptoms of severe malaria. The PfEMP1 are exposed to the immune system during infection and are therefore excellent vaccine candidates for use in an approach to prevent severe disease. A key question, however, is whether their extensive diversity precludes them from forming components of the malaria vaccines of the future?

Age-specific patterns of DBLα var diversity can explain why residents of high malaria transmission areas remain susceptible to Plasmodium falciparum blood stage infection throughout life

“…Variation in PfEMP1 is considered a key driver of transmission dynamics within and between hosts due to immune evasion ( Gupta and Day, 1994 ). Expression of different groups of var genes identified by chromosomal locations has also been associated with virulence in case-control studies and transcriptomic analyses, with a conserved subset of PfEMP1 associated with severe disease ( Lavstsen et al, 2012 ; Bengtsson et al, 2013 ; Rorick et al, 2013 ; Lau et al, 2015 ; Bernabeu et al, 2016 ; Jespersen et al, 2016 ; Magallón-Tejada et al, 2016 ; Lennartz et al, 2017 ; Tonkin-Hill et al, 2018 ). Our previous work has explored var gene diversity in infected children by focusing on the near ubiquitous Duffy-binding-like alpha domain (DBLα) region of var genes as a population genetic marker ( Chen et al, 2011 ; Day et al, 2017 ; Ruybal-Pesántez et al, 2017 ).…”

Recent advances in the molecular epidemiology of clinical malaria

“…So far, the high diversity of PfEMP1 has precluded this family of molecules from being considered a serious vaccine target. However, the discovery that certain disease manifestations are associated with the expression of restricted subsets of PfEMP1 variants has opened up the debate of whether an anti-disease or anti-virulence vaccine in fact might be a feasible option 19 . One of the first and so far most robust examples is the involvement of a particular PfEMP1 variant in pregnancy-associated malaria, mediated by the binding of VAR2CSA-expressing iRBCs to placental chondroitin sulfate A (CSA) 20 .…”

“…As such, the recent discovery that a much smaller gene subset, those containing specific domain types called CIDRα1, and their binding to the endothelial protein C receptor (EPCR) appeared to be associated with cerebral malaria caused great excitement 23 – 26 . In fact, confidence in the importance of this interaction underlying severe infection outcomes is such that it is now being promoted as a potential anti-disease vaccine target 19 .…”

Identifying functional groups among the diverse, recombining antigenic var genes of the malaria parasite Plasmodium falciparum from a local community in Ghana

“…Despite this vast sequence diversity, it nevertheless seems unlikely that each var sequence variant is functionally unique. Functional classification of var diversity is of clinical interest for the purpose of designing effective monitoring and intervention (e.g., for studying the strain structure of the parasite [ 15 ], or for the possibility of developing a var -based vaccine [ 16 ]). However, mapping the vast number of var sequence types to a smaller number of meaningful functional types has remained a major challenge in the field.…”

“…A major motivation within the field currently is to pursue links between var geneotype and disease phenotype, in the hope that interventions—in particular vaccination—may be able to specifically target severe-disease associated Pf EMP1 functions [ 16 ]. In light of this goal, one limitation that all current var classification schemes share is that they assume similar sequences should have similar adhesive properties.…”