From a distance, malaria looks like a disease that we should have eradicated by now.  Scientists have known for many years that most dangerous malaria cases are caused by the Plasmodium falciparum parasite.  This parasite is transmitted to humans through the bite of an Anopheles mosquito, and has a complicated but well-understood lifecycle within its human host, involving invasion of both the liver and the blood [1].  In humans, malaria causes fever, vomiting, headaches, and general achiness, but complications including brain damage, seizures, and red blood cell damage are responsible for most human deaths.  With so many potential places to target malaria treatment – in the human liver, in human blood, or in the mosquito that carries the parasite from person to person – why did it still kill 655,000 people in 2010?

To be certain, malaria is on the decline.  In the mid-19th century, over 90% of the world population was at risk for malaria.  Figure 1 shows how this risk has declined, particularly in recent years; malaria today is primarily a concern in South America, Sub-Saharan Africa, and Southeast Asia.

Figure 1. Malaria prevalence has decreased since the 19th century.  This map shows the extent of malaria in the mid-19th century, before 1946, in 1967, and in 2010. [2]

Vector Control: Don’t kill the parasite, kill the host

Mosquitoes are the vector, or delivery vehicle, that carry malaria parasites from one person to another.  One of the key factors contributing to the decline in malaria was the use of vector control: practices designed to stop the parasite before it even reaches humans, while it’s still living in the mosquito. The major vector control method is the use of bed nets.  Sleeping under tightly-woven, insecticide-coated nets greatly reduces the chance that a person will be bitten and infected in the night, when Anopheles mosquitoes are most active. These nets aren’t perfect, but pre-treating bed nets with insecticide greatly improves chances of killing hungry mosquitoes intent on finding a way around the bed net.

Another vector control strategy is spraying insecticides like dichlorodiphenyltrichloroethane (DDT) or pyrethroids on the interior walls of buildings in malaria-affected regions, a technique known as indoor residual spraying.  Though first used to combat malaria, DDT became a popular insecticide for agricultural pest control in the mid-20th century.  This led to increased resistance to DDT, making it less effective against malaria and in agriculture.  Pyrethroids have more recently become the anti-malarial insecticide of choice.  Due to their low toxicity, high kill rate, and repellent effect, pyrethroids are now the most-used class of insecticide, whether in the developing world or in cans of Raid on your local CVS shelf.

The World Health Organization (WHO) recently released a report citing the importance of these and other vector control methods in eradicating malaria [2].  The report also highlighted the challenges posed by increases in insecticide resistance in mosquitoes, meaning populations of mosquitoes that are no longer effectively controlled by an insecticide dose that was previously sufficient [3].  The report warns that without improved vector control, malaria could come back with a vengeance (Figure 2).

Figure 2. Resistance to insecticides used in controlling malaria transmission is on the rise, with most malaria-affected countries reporting resistance to at least one insecticide. [2]

Resistance arises when mosquitoes are exposed to the same insecticide for years on end.  Some small percentage of mosquitoes will be able to thrive even in the presence of insecticide.  Over generations, mosquitoes that can thrive even in the presence of insecticide will produce more offspring than those that get sick and die.  Even if these thriving mosquitoes are only a tiny fraction of the population at first, since they are able to survive when insecticide-affected mosquitoes cannot, these thriving mosquitoes will breed and reproduce until they take over the population, rendering a formerly useful insecticide worthless for malaria prevention.

The report presented a variety of options for public health officials and countries looking to avoid this resistance.  Rotating insecticides in a region – using one for a year then switching to another – challenges the mosquitoes in different ways, preventing the buildup and subsequent spread of resistance through one insecticide-specific mechanism.  It is also theoretically possible to use combination insecticide treatment – spraying two insecticides that kill mosquitoes in different ways to prevent a mosquito that can evade death by one insecticide from taking over.  Unfortunately, no successful combinations have yet been validated.

Other efforts to combat malaria

In addition to improving vector control, scientists are also attempting to fight the parasite itself on multiple fronts.  Academics and companies continue to develop more effective drugs for treating malaria in humans who have already been infected, though an effective, well-tolerated drug known as artemesinin already exists.  The biggest challenge with treating infected humans is the logistics: antimalarial drugs are expensive, difficult to widely distribute in undeveloped areas, and unstable – most must be used within one year.

The cost, in particular, has led to a proliferation of fake drugs – a recent study in the scientific journal The Lancet Infectious Disease suggests that up to one third of antimalarial drugs circulating in the most severely affected regions are counterfeit [4].  These fake drugs not only fail to help the patients taking them, but can also propagate Plasmodium drug resistance in general because they provide such a weak dose of the drug.  This dose is not enough to kill the parasites entirely, but it will make some of the parasites sick and unable to breed as quickly.  Like the mosquitoes described above, some parasites will thrive in the presence of this drug, breeding more quickly than the drug-affected mosquitoes and eventually taking over the population.  These fake drugs will increase resistance without even killing the parasites like the full strength drugs would do!

Just as mosquitoes have developed resistance to commonly-used insecticides, the malaria parasite has proven its ability to overcome successive generations of full-strength antimalarial drugs. Even now, the WHO has called for artemisinin to be used only in combination with previous generation products like chloroquine that have different mechanisms of action in the hopes of preserving the effective lifespan of the treatment. However, just as reports of insecticide resistance have sprung up in Africa, so too have reports of artemisinin resistance in Southeast Asia.

Looking forward, while continued investment in all forms of malaria control and treatment will be critical in staying ahead of the disease, vector control is likely to be the lowest-cost, highest-efficacy method of reducing disease burden and contributing to the eventual eradication of malaria.  Fortunately, a number of exciting new vector control methods are currently in development, including longer-lasting insecticide formulations, and the targeted deployment of Wolbachia pipientis, a bacteria that infects malaria-carrying mosquitoes and can prevent transmission by blocking the development of Plasmodium falciparum within the mosquito [5].

Laura Strittmatter is a graduate student in Chemical Biology at Harvard University.

References

[1] Life Cycle of the Malaria Parasite (National Institute of Allergy and Infectious Disease) <http://www.niaid.nih.gov/topics/malaria/pages/lifecycle.aspx>

[2] Global Plan for Insecticide Resistance Management in Malaria Vectors (World Health Organization Global Malaria Programme) <http://whqlibdoc.who.int/publications/2012/9789241564472_eng.pdf>

[3] Malaria Surge Feared (Amy Maxmen, Nature) <http://www.nature.com/news/malaria-surge-feared-1.10643>

[4] Third of malaria druge “are fake” (Michelle Roberts, BBC) <http://www.bbc.co.uk/news/health-18147085>

[5] Wolbachia: The Difference Between a Nuisance and a Threat? (Jamie Schafer, Small Things Considered) <http://schaechter.asmblog.org/schaechter/2011/09/wolbachia-the-difference-between-a-nuisance-and-a-threat.html>

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