Abstract
All the symptoms and pathology of malaria are caused by the intraerythrocytic stages of the Plasmodium parasite life cycle. Because Plasmodium parasites cannot replicate outside a host cell, their ability to recognize and invade erythrocytes is an essential step for both parasite survival and malaria pathogenesis. This makes invasion a conceptually attractive vaccine target, especially because it is one of the few stages when the parasite is directly exposed to the host humoral immune system. This apparent vulnerability, however, has been countered by the parasite, which has evolved sophisticated molecular mechanisms to evade the host immune response so that parasites asymptomatically replicate within immune individuals. These mechanisms include the expansion of parasite invasion ligands, resulting in multiple and apparently redundant invasion "pathways", highly polymorphic parasite surface proteins that are immunologically distinct, and parasite proteins which are poorly immunogenic. These formidable defences have so far thwarted attempts to develop an effective blood-stage vaccine, leading many to question whether there really is an exploitable chink in the parasite's immune evasion defences. Here, we review recent advances in the molecular understanding of the P. falciparum erythrocyte invasion field, discuss some of the challenges that have so far prevented the development of blood-stage vaccines, and conclude that the parasite invasion ligand RH5 represents an essential pinch point that might be vulnerable to vaccination.
Highlights
Throughout their extraordinarily complex life cycle, Plasmodium parasites must navigate a wide range of intracellular and extracellular environments in both vertebrates and invertebrates
Initial contacts between the merozoite and erythrocyte can occur at any point on the merozoite surface, which are rapidly followed by the reorientation of the polar merozoite such that its apical end directly apposes the erythrocyte membrane
This allows the parasite to deploy a series of specialised apically located secretory organelles: rhoptries, micronemes, and dense granules. These organelles discharge their contents in a regulated and ordered schedule during and immediately after the invasion process at the site of contact [3,4,5]. Ligands released in this manner interact with erythrocyte surface receptors to form an electron-dense thickening of the erythrocyte membrane at the nexus of erythrocyte– merozoite contact
Summary
Are MSPs often highly polymorphic, making them challenging targets, they generally have poorly defined functions. The expansion of the EBA and RH families in P. falciparum and the consequent redundancy and complexity that it creates means that several of these ligands would have to be simultaneously targeted to effectively reduce or block all invasion This makes the development of such a vaccine technically challenging, initial trials with PfRH and PfEBA combinations do show some promise [32,43,44]. It is worth pointing out that the design of some Phase IIa vaccine trials where subjects are experimentally infected can set a very high bar for efficacy [45] In these trials, curative drug treatment must be applied as soon as parasites are detected by PCR in the blood, for quite understandable health and ethical reasons. It is likely that we will either have to abandon these complex targets, or change the design of vaccine trials to allow us to better detect their effects, for example, by including dose escalation studies to enable the detection of effects that may be visible only at low starting parasitemias
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