A vaccine targeted specifically to prevent cerebral malaria – is there hope?

KEYWORDS:

• Malaria
• Plasmodium falciparum
• cerebral malaria vaccine
• PfEMP1
• ICAM-1
• EPCR

1. Introduction

Malaria remains a major infectious disease burden on health in large parts of the world. The disease is estimated to claim close to half a million lives a year, in addition to untold suffering, mainly among young children and pregnant women in Africa [1]. Severe and fatal forms of malaria include cerebral malaria, severe malarial anemia, and placental malaria. These complications are largely restricted to infections by just one of the several species of malaria parasites that can infect humans: Plasmodium falciparum. This parasite is therefore the current main target in the fight against malaria, including vaccine development, and the focus of this editorial.

An efficacious malaria vaccine could be a decisive game changer in the battle, and induction of sterile immunity to malaria by vaccination in an animal model was demonstrated decades ago [2]. However, despite enormous efforts and encouraging results from experimental immunization of human volunteers [3,4], it has not (yet) been possible to achieve solid and durable protection against genetically diverse parasites with a practically deployable vaccine. The only vaccine that has reached the market so far, RTS,S/AS01 (Mosquirix) licensed in 2015, offers only fairly modest and relatively short-lived protection [5]. While intense efforts to improve the performance of this vaccine are in progress, several other vaccines are also at various stages of preclinical and clinical development.

Malaria vaccines have traditionally been divided into three major types. The preerythrocytic stage vaccines (like RTS,S) target the early stages of the infection to stop the parasites before they reach the blood to cause clinical symptoms. Asexual blood-stage vaccines aim to disrupt the multiplication cycle in the blood by inhibiting parasite (re)invasion of uninfected erythrocytes, while transmission-blocking vaccines have the goal of interrupting parasite development in the mosquito vectors after they feed on infectious hosts. Regardless of the antigens employed, the life cycle stages targeted, and the effector mechanisms involved, these malaria vaccines aim to break parasite transmission and ultimately to eradicate the disease. Like vaccines in general.

2. Vaccination against disease rather than infection – the placental malaria paradigm

There is evidence to suggest that it may be possible to vaccinate against the disease rather than against the infection per se, i.e. to remove the symptoms and relieving the pathology of malaria without necessarily breaking parasite transmission. This approach would allow regular boosting of the vaccine-induced immune response by natural exposure, possibly lengthening the timespan of protection, which has been disappointingly short with current malaria vaccines. The leading example of this approach is development of vaccines designed to prevent placental malaria [6].

Placental malaria is the consequence of selective accumulation of infected erythrocytes in the intervillous space, which leads to inflammation and compromises the exchange of molecules (nutrients, antibodies, waste products etc.) between the mother and her baby. The results are morbidity and mortality related to maternal anemia, intrauterine growth retardation, prematurity, and low birth weight of the infant [7]. The aim of the vaccines designed to protect specifically against placental malaria is to prevent the sequestration of the infected erythrocytes in the placenta and thereby facilitating their removal by the spleen. The target of the vaccine is the so-called ‘minimal binding-domain’ of the parasite antigen VAR2CSA on the infected erythrocyte surface. VAR2CSA binds specifically to onchofetal chondroitin sulfate, normally expressed only in the placenta. VAR2CSA belongs to the ~60-member PfEMP1 family that mediates infected erythrocyte adhesion to a number of different vascular host receptors [8]. Only one PfEMP1 variant is expressed on the infected erythrocyte at a time, but the parasites can switch among the different members, yielding many opportunities for infected erythrocyte sequestration in many different tissues. However, the receptor for VARCSA is restricted to the placenta, and parasites expressing VAR2CSA therefore cannot survive in nonpregnant hosts (as they have nowhere to sequester). Consequently, young women have no immunity to VAR2CSA when they get pregnant for the first time, regardless of any PfEMP1-specific immunity they may have acquired earlier in life. Once exposed to VAR2CSA during pregnancy, protective immunity is acquired, and placental malaria is therefore mainly a problem during the first one or two pregnancies. The goal of the VAR2CSA-based vaccines is thus to establish IgG-mediated immunity to inhibit VAR2CSA-specific adhesion of infected erythrocytes in the placenta before the first pregnancy.

3. Vaccinating against cerebral malaria – or against severe malaria?

Can the same approach be taken to vaccinate specifically against cerebral malaria, which is a malaria complication with very high mortality? Before answering this question, it should be realized that an important component in the pathogenesis of P. falciparum malaria in general, and perhaps the key event in the progression to severe disease, is the inflammation and circulatory disturbances that follow from adhesion of infected erythrocytes in the vasculature [9]. When this occurs in tissues and organ systems that are critical for survival, the consequences can be serious – even fatal. The most prominent example of this is cerebral malaria, where adhering infected erythrocytes obstruct brain blood flow and cause inflammation in the cerebral microvasculature (as well as in other vascular beds). If this adhesion could be prevented, it is likely that cerebral malaria would also be. In principle, therefore, it should be possible to develop a vaccine to prevent cerebral malaria, based on the same principles and approaches that are currently being applied to develop a vaccine against placental malaria.

Until recently, it was unclear which PfEMP1 variants mediate the adhesion of infected erythrocytes in cerebral malaria patients, and to which receptors they bind. However, several lines of evidence are converging to indicate that specific PfEMP1 proteins and host receptors are involved, and that neither is restricted to the brain or to cerebral malaria [8]. This is quite unlike the situation with placental malaria, which as mentioned appears to be precipitated by a single PfEMP1 antigen (VAR2CSA) binding to a single receptor (onchofetal chondroitin sulfate), mediating infected erythrocyte sequestration in just one tissue (the placenta), and therefore completely restricted in time (pregnancy). With that in mind, let us consider the question posed in the title of this editorial.

It is becoming increasing clear that P. falciparum parasites causing severe malaria (apart from the special case of placental malaria) share the ability to bind to a particular molecule in the vasculature called endothelial protein C receptor (EPCR) [10]. This receptor normally mediates the cyto-protective effects of activated protein C that is central to vascular homeostasis, but that function is disrupted by the interaction of EPCR with adhering infected erythrocytes [11]. The P. falciparum ligand mediating infected erythrocyte adhesion to EPCR is PfEMP1, and more specifically a particular PfEMP1 building block called CIDR-α [10]. Two main functional types of CIDR-α domains can be distinguished: those that bind the host receptor CD36 and those that bind EPCR. Remarkably, only the latter appear involved in the pathogenesis of severe malaria [12–14]. It is thus tempting to speculate that blocking of EPCR-specific adhesion of infected erythrocytes by vaccination with the relevant CIDR-α domains would lead to protection not only against cerebral malaria, but also against much of childhood severe malaria in general. It is not yet known whether this will be feasible. EPCR-binding CIDR-α domains show substantial inter-clonal sequence variation, but as the binding domain nevertheless remains structurally conserved, there is certainly hope that this variation can be overcome [15]. If it can be achieved, however, will blocking of infected erythrocyte adhesion to this particular receptor be enough to curb severe malaria in general?

PfEMP1 are large multi-domain molecules, and all PfEMP1 have several domains in addition to their CD36- or EPCR-binding CIDR-α domain – all known to, or potentially able to, interact with host receptors [8], although their clinical relevance is not fully resolved. In any case, multiple receptor interactions probably act in concert allowing each PfEMP1 to bind several receptors simultaneously, and this is likely to contribute to pathogenesis. An important example is the dual interaction of certain PfEMP1 proteins with both EPCR (via CIDR-α) and with ICAM-1 (via another type of domain called DBLβ) [16]. These ‘double-binders’ are more common in cerebral malaria than in other types of severe malaria. The receptor-binding functionality of the adhesive domains of PfEMP1 restricts their diversity, and this appears to be particularly so for the ICAM-1-binding sites in the DBLβ domains found in cerebral malaria patients [16,17]. It remains an unanswered question, whether blocking the interaction with EPCR and/or ICAM1 will suffice to prevent the infected erythrocyte sequestration leading to cerebral malaria. Resolving this and other important questions regarding the pathogenesis and pathophysiology of severe P. falciparum malaria are made difficult by the lack of animal models that adequately reproduce key elements of the human disease [18]. Research to overcome this important obstacle should be high priority.

4. Is it worth it?

P. falciparum malaria continues to claim a completely unacceptable number of lives. The disease remains a major obstacle to human and economic progress, particularly in Africa, and the encouraging progress in the fight against malaria in recent years is seriously endangered by spreading drug resistance, insecticide resistance, and other threats. An efficacious malaria vaccine would be a decisive new tool to win the battle. There has been an increasing focus on preerythrocytic and transmission-blocking vaccines lately, as the diversity of most asexual blood-stage antigens, not least of PfEMP1, is considered an insurmountable obstacle by many. However, given the fact that the results of efforts to develop such vaccines have been largely disappointing to date despite enormous investments, we believe that it is too early – and indeed irresponsible – not to ensure that alternative approaches such as those outlined above can continue to be pursued energetically. A very recent paper shows that we are not alone [19].

Clinical efficacy trials of vaccines aimed at preventing severe disease are inherently more complicated than trials of vaccines aimed at preventing infection per se. The ongoing clinical trials of VAR2CSA-based vaccines against placental malaria are likely to provide important insights that will benefit future trials of this kind. In addition, available evidence suggests that adequately powered clinical trials of vaccines aimed to protect against severe malaria in children are within practical reach [20].

In conclusion: tremendous progress has been made, there is hope, and the potential gains are immense.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The manuscript was not funded.