Open access peer-reviewed chapter

Plasmodium vivax and Plasmodium ovale in the Malaria Elimination Agenda in Africa

Written By

Isaac K. Quaye and Larysa Aleksenko

Submitted: September 29th, 2020 Reviewed: February 26th, 2021 Published: July 21st, 2021

DOI: 10.5772/intechopen.96867

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Abstract

In recent times, several countries in sub-Saharan Africa have reported cases of Plasmodium vivax (Pv) with a considerable number being Duffy negative. Current efforts at malaria elimination are focused solely on Plasmodium falciparum (Pf) excluding non-falciparum malaria. Pv and Plasmodium ovale (Po) have hypnozoite forms that can serve as reservoirs of infection and sustain transmission. The burden of these parasites in Africa seems to be more than acknowledged, playing roles in migrant and autochthonous infections. Considering that elimination and eradication is a current aim for WHO and Roll Back Malaria (RBM), the inclusion of Pv and Po in the elimination agenda cannot be over-emphasized. The biology of Pv and Po are such that the same elimination strategies as are used for Pf cannot be applied so, going forward, new approaches will be required to attain elimination and eradication targets.

Keywords

  • Plasmodium vivax transmission
  • Plasmodium ovale
  • asymptomatic transmission
  • sub-Saharan Africa

1. Introduction

Malaria elimination is defined as interruption of local transmission of malaria in a defined area [1, 2]. Within a geographical demarcation, malaria transmission is heterogenous ranging between high, intermediate or low [3, 4]. This means that elimination efforts must be defined with respect to the geographical area, and interventions targeted to specified strata to achieve elimination goals [5, 6]. Data for such targeted intervention can come from the use of sensitive and specific surveillance diagnostic tools that can discriminate between species, including asymptomatic infections. In Africa, current efforts of intervention by National Malaria Control Programs and recommendation by WHO and Roll Back Malaria (RBM) are focused mainly on Plasmodium falciparum (Pf) with little to no attention on non-falciparum species although the latter are established to be present in all of Africa [7, 8]. Clearly if elimination is envisaged based on the target of RBM, then inclusion of all human Plasmodium species in the elimination agenda is relevant. Non- falciparum Plasmodial species are more complicated in their transmission than Pf [9, 10, 11]. Especially, Plasmodium vivax (Pv), that is the most prevalent in the world and the two sympatric species of Plasmodium ovale (Po), Plasmodium ovale curtisi and Plasmodium ovale wallikeri both of which cause severe disease and have hypnozoite stages in their transmission cycle as Pv [12, 13, 14, 15]. The inclusion of all species should be well planned in such a way that it does not take away from the efforts being made to reduce Pf transmission but to go hand in hand. The transmission dynamics of these species must be well understood so that measures tailored to them are put in place. Here aspects of the biology of the parasites are elaborated so they are put in perspective with regards to elimination.

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2. Biology of Pv and Po

Plasmodium species are obligate intracellular parasites that infect Anopheles mosquitoes in the sexual life cycle and humans in their asexual life cycle [16]. In humans, replication takes place in the liver hepatocytes, following inoculation by an infected Anopheles mosquito into the skin, and migration of the parasite through the capillaries into the blood stream and then to the liver parenchyma cells [17]. This pattern of infection is similar in all known human Plasmodium parasites which currently are P. falciparum, P. vivax, P. ovale curtisi, P. ovale wallikeri, P. malariae and P. knowlesi [18].

Outside of Africa, Pv is the predominant parasite, but even so the phenotypic characteristic from individuals infected with the parasite from different populations appear to differ. One of the most important differences between plasmodial species infecting humans is the ability of Pv and Po to relapse after the cure of the original infection [9, 12]. A proportion of sporozoites do not undergo immediate development in the invaded hepatocytes. Instead, they remain dormant in the liver as hypnozoites for prolonged periods of time before developing and causing recurrent infection [19]. P. vivax strains from different geographical areas show widely different relapse patterns, reflecting evolutionary adaptation to local environmental conditions that optimize transmission potential of the parasite [20]. In Africa, it had previously been generally accepted that because of the high prevalence of ACKR1 polymorphism, individuals of African descent are resistant to infection by the parasite [21]. Recent evidence of Pv presence in nearly the whole of Africa, indicates that Pv may have other mechanisms for invasion [22]. Advancing research into the parasites’ biology and mechanism of invasion is necessary for elimination and eradication. Although Po is not limited by the Duffy antigen polymorphism, the shared biology of hypnozoites and their relapse makes it of equal concern in malaria elimination. What is palpably clear is that reporting of these two parasites from countries in Africa, appears not to reflect the true prevalence rate as reporting is largely passive and not active.

2.1 Parasite transmission

Transmission of the parasite defines the processes that the parasite takes to complete a life cycle [1]. The process in the Anopheles vector is referred to as sporogony while that in humans is referred to as schizogony. Schizogony begins when liver schizonts which contain multiples of merozoites mature and burst with subsequent release of the merozoites into the blood stream [23]. The merozoites invade young reticulocytes that have the surface marker CD71(CD71+) [24] where they mature into trophozoites. The trophozoites mature into blood stage schizonts containing multiples of merozoites, burst the reticulocytes and initiate a new cycle of blood stage transmission. Some of the merozoites mature into male and female gametocytes that are picked by female Anopheles mosquitoes when mature, to begin the sporogonic cycle [1]. In Pv and Po some of the liver schizonts remain dormant for weeks, months or years and then get activated to initiate a new infection in the reticulocytes [16]. It is not clear what exactly triggers the reactivation, although new Plasmodium and other infections and inflammation, have been suggested as contributory [9, 25]. The subsets that remain in the liver are the hypnozoites, and the reactivation process is called ‘relapse’. The activation of hypnozoites is reported to cause most of the blood stage infections [26]. It is not clear whether the under-reporting of Pv and Po infections in Africa is attributed to hypnozoites relapsing or lack of tools or focus for targeting these species for detection.

It has been reported that the hypnozoites are not only derived from liver parenchyma cells, but also from bone marrow parenchyma that abounds in young and CD71+ reticulocytes [24]. It has been shown that the bone marrow is enriched in gametocytes extravascularly, while the liver is enriched with tissue schizonts in the sinusoids compared to peripheral blood [24]. In addition, a small number of parasites are seen in the vasculature of the lungs as opposed to those in the bone marrow and liver which are extravascular [27]. The hypnozoite stages are particularly troubling because chemotherapy against them with the use of primaquine is restrictive due to glucose-6-phosphate dehydrogenase deficiency and CYP2D6 polymorphism [28]. Also, it has been reported that primaquine may not be efficacious against some strains of the hypnozoite stages [29]. Nevertheless, radical cure with primaquine at least can go a long way in the agenda towards elimination.

2.2 Hypnozoite stages

Previously there was no direct evidence of hypnozoite stages of Po, however recent reports have clearly shown that such stages indeed exist for both Po curtisi and Po wallikeri [30]. The sub-species of the parasite contribute to the transmission dynamics and need to be fully interrogated for markers and drug targeting. Another unique biology of the parasite is the early emergence and maturation of gametocytes in the blood. While gametocytes for Pf, Pm mature in about 10–12 days, for Pv and Po, gametocytes are seen between 3 to 5 days following the first documentation of parasites in the peripheral blood [1, 16, 23]. This means even before any symptoms of infection are seen the parasite would have been transmitted if female Anopheles mosquitoes fed within the period. In this case an intervention in the transmission process can be missed. It maybe that these traditionally unseen parasites, contribute to the low parasitemia usually seen with these infections and why Pv and Po infections are characterized as benign although they can cause as much severe disease as in Pf infections.

2.3 Transmission dynamics

In regions outside of sub-Saharan Africa (SSA) where Pf and Pv coexist, mixed-species infections are common [31]. In such situations, there are observed shifts in the dominant parasite towards Pv as Pf transmission declines. Surveys usually report rates less than 2% and yet careful clinical studies record rates of up to 30% and this figure is even higher when PCR detection methods are used. This trend means that in a couple of years to come, without effective and necessary interventions, when the Pf burden has been significantly reduced in Africa, Pv and Po infections could constitute the most dominant Plasmodium species on the continent. We observe that countries that were on course for Pf elimination such as Botswana, eSwatini, and South Africa have seen changes recently, part of which is due to Pv and Po. Concurrent infections with different Plasmodium species may have important implications on the host response and development of cross-species immunity. The potential for Pv to attenuate Falciparum malaria obviously requires further characterization and has significant implications for vivax-only vaccination strategies, and the deployment of drugs such as chloroquine, which has lost efficacy against Pf but still retain it against Pv. The transmission of the parasite in Duffy negative individuals raises serious concern as essentially Pf is the only targeted species in the elimination agenda in Africa, with minimal consideration for Pv and Po.

2.4 What is needed currently on Pv and Po transmission?

As noted previously, Pv and Po can cause severe disease [13, 15]. The most characteristic of Pv are acute respiratory distress syndrome (ARDS), anemia and decreased oxygen saturation in both children and adults [32, 33]; clinical conditions which are also seen in Po infections [34, 35, 36]. The respiratory illnesses are associated with high mortality, with a higher risk in women. In the cited Po cases of ARDS, the patients were also HIV positive, so it is not clear if HIV facilitated development to full blown ARDS or not [32, 37]. The new tissue sequestration sites of Pv and Po mention previously, which are out of routine diagnostic procedures, means the task of eliminating Pv and Po is clearly not an easy one. When the unique biology of Pv and Po vis-à-vis the evidence of their presence in Africa are considered, there is a need for a paradigm shift regarding Pv and Po research by putting in place the following:

  1. Sensitization of National Malaria Control Programs (NMCPs) to the menace of the two parasites in asymptomatic and symptomatic infections

  2. Provision of baseline and standardized tools for sample collection, detection and assays for Pv and Po towards the elimination of the parasites.

  3. Measures for all individuals irrespective of age in Africa to be at reduced risk to Pv and Po infections

  4. De-escalation of the burden of Pv and Po, through the utilization of novel and available tools that can be integrated into malaria control and elimination agenda in sub-Saharan Africa.

  5. Crosstalk between NMCPs and researchers as well as institutions engaged in malaria research.

  6. Creation of fora for exchange of knowledge and resources between Pv and Po focused scientists in Africa and globally, to facilitate progress in control and elimination activities.

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3. Conclusion and future perspectives

The presence of Pv and Po in Africa is certain. Malaria control programs generally focus on providing good vector control, early diagnosis, and access to effective antimalarial regimens, preferably with anti-gametocyte activity to reduce transmission. All these tools cannot be optimally employed without a knowledge of the transmission dynamics of all parasites within a community or country. Re-engaging the focus of NMCPs on non-falciparum malaria that harbor hypnozoites and that potentially could be a significant problem in the very near future is a necessity. Pooling of resources regionally and internationally are key elements for the fight against reducing the burden of non-falciparum malaria and their elimination. It is important that NMCPs and researchers from Universities and Research Institutions engage in crosstalk to facilitate accurate detection and surveillance, and generate the human resource required for sustaining these efforts.

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Acknowledgments

The authors acknowledge the patience and support of the Intech Open team and our entire family in the write up.

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Conflict of interest

The authors declare no conflict of interest.

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Written By

Isaac K. Quaye and Larysa Aleksenko

Submitted: September 29th, 2020 Reviewed: February 26th, 2021 Published: July 21st, 2021