Why Vivax Malaria Represents a Serious Problem for Malaria Eradication

In mid-2015, the World Health Organisation (WHO) adopted one of the most ambitious malaria eradication programmes ever, a strategy covering the period from 2016 to the end of 2030. The main objective of this programme is to eliminate malaria from 35 countries and to reduce the number of cases and the associated mortality globally by 90%.

Malaria in humans caused by Plasmodium vivax, a parasite species that has been neglected for many years, is a very serious problem

However, these targets will not be achieved unless we tackle a very serious problem: malaria in humans caused by Plasmodium vivax, a parasite species that has been neglected for many years. Vivax malaria has traditionally been considered a more benign form of the disease than that caused by infection with P. falciparum. This perception has changed in recent years owing to the increase in the number of severe cases and deaths associated with P. vivax throughout the regions where malaria is endemic.

The researcher Carmen Fernández working at the lab.

An estimated 14 million people in the world are infected with P. vivax and some 2.5 billion live in areas where there is a risk of infection

Today, an estimated 14 million people in the world are infected with P. vivax and some 2.5 billion live in areas where there is a risk of infection, making it geographically the most widely distributed cause of human malaria.

Vivax malaria is much more difficult to control than disease caused by P. falciparum

And why does P. vivax represent a serious problem for malaria eradication? The answer to that question can be found in some of the distinct characteristics of the biology of the parasite and the behaviour of its insect vector, which make vivax malaria much more difficult to control than disease caused by P. falciparum. Among these specific features, I would like to highlight the following:

1. The presence of hypnozoites, a latent (dormant) form of the parasite that develops in the liver, which can reactivate weeks or months after the primary infection and cause clinical relapses that present the same characteristics as primary infections. Relapses account for more than half of the clinical cases currently reported. Moreover, as this liver stage cannot be detected using currently available diagnostic methods, it constitutes a silent reservoir of the disease.  Ultimately, to eradicate malaria, we need to develop new diagnostic methods capable of detecting hypnozoite carriers.

Treatment requires 14 daily doses and in many cases patients do not complete the regimen

2. Primaquine is the drug currently used to eliminate hypnozoites from the liver. Treatment requires 14 daily doses and in many cases patients do not complete the regimen, thereby favouring the transmission of the disease and making it more difficult to control.  The problem is further exacerbated by the adverse effects associated with primaquine, particularly in patients who have a severe deficiency of the enzyme glucose-6-phosphate dehydrogenase (G6PD), in whom the drug triggers hemolysis. Primaquine cannot, therefore, be administered to pregnant women or children because of the risk that the patient might have this enzyme deficiency. Hence, the need to develop new drugs.

3. The number of circulating parasites is much lower in people infected with P. vivax than in those infected with P. falciparum, making it much more difficult to diagnose vivax infection using current methods. In fact, today, we are only seeing the tip of the iceberg because most P. vivax infections are submicroscopic and many infected patients are asymptomatic.

Most P. vivax infections are submicroscopic and many infected patients are asymptomatic

4. During the blood stage of the infection, P. vivax preferentially, if not exclusively, invades immature red cells blood called reticulocytes. This characteristic is thought to be one of the greatest obstacles to achieving a stable in vitro culture of P. vivax, a task that has proved impossible to date. This inability to maintain a stable culture has, in turn, made it difficult for scientists to do the functional studies that would allow them to gain a better understanding of the parasite’s biology.

5. For this reason, little is known about the molecular basis of vivax malaria. Our group has been working on this problem for many years, initially on the description of the first multigenic family implicated in the virulence of the parasite and more recently on determining the role of the spleen and bone marrow during infection. We have demonstrated the presence of the parasite in both of these organs. We believe that this will make it even more difficult to eradicate malaria because the parasite can “hide” in organs with slow blood flow rates that limit drug access.

Presence of P. vivax parasite in bone marrow. Author: Carmen Fernández.

6. The mosquito that transmits P. vivax also has characteristics that contribute to the greater transmission of vivax malaria. First, by adapting to colder climates, it has achieved wider geographical distribution. Second, it bites outdoors, making it more difficult to prevent exposure using traditional methods, such as insecticide impregnated bed nets.

All of these problems were discussed at the 6th International Conference on Plasmodium vivax Research held last June in Manaus, Brazil. Among the technological advances presented at that event were humanised mice with human liver tissue that can support liver stage malaria, and research on new drugs designed to eliminate hypnozoites. Attendees also heard about the promising results obtained with tafenoquine, a new drug that is similar to primaquine but is administered as a single dose.

6th International Conference on Plasmodium vivax Research, June 2017, Manaus, Brazil.

The methods currently used to control and eradicate vivax malaria are inadequate

However, it was also clear that the methods currently used to control and eradicate vivax malaria are inadequate. As a result, there is a new interest in funding scientific studies on this species and a growing awareness of the need to continue investigating the biology of this parasite, to develop more effective diagnostic methods, and to develop new drugs and other control tools that will make it possible to accelerate malaria eradication. #timetogoforvivax

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