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Malaria: the long march to eradication

World Malaria Day was April 25, but it deserves more than the attention of just one day. The disease has been with us for more than ten million years and affects organisms as diverse as primates, porcupines, and snakes, so it’s worthwhile taking a moment to consider the amazing progress that’s been made toward containment — as well as how devastating it remains.

Infection and illness

Malaria is a bloodborne disease transmitted by mosquitoes and caused by single-celled parasites of the genus Plasmodium. It’s characterized by cyclical fevers; and because the parasites inhabit red blood cells, and burst free after completing each round of their life-cycle (causing fever spikes as the immune system reacts to the bits of burst cell), repeated infection can result in anemia. In more serious cases, infected red blood cells become sticky and adhere both to uninfected blood cells and the walls of capillaries in the brain. This can block circulation, resulting in coma, seizures, and occasionally brain damage or even death.

An infection starts with a mosquito bite, usually by a female Anopheles. The mosquito spits a little as she’s feeding, releasing the sporozoite stage of the parasite along with her saliva. Once in the body, the parasites will glide or slither to reach the closest blood vessel, and from there try to reach the liver. Sporozoites are fairly delicate and die within minutes to hours in the blood, but in the liver they proliferate massively. A week to ten days following a bite, several thousand merozoites are coordinately released into the bloodstream to infect red blood cells. Over the next 48 to 72 hours they mature and eventually undergo mitosis and cell-division, culminating with synchronous bursting from the infected red cells, release of further merozoites into the bloodstream and infection of new blood cells, and another fever spike (a video of parasite egress and reinvasion can be found here).

Blood-stage parasites are typically asexual. However, as an infection progresses, signals will occasionally be sent that instead induce production of the sexual stages — male and female gametocytes. These can be uptaken by a mosquito during feeding, eventually resulting in transmission to another host.

C****ures and containment

There are two ways to get rid of malaria: kill the parasites or kill their mosquito vector. In fact, until the 1950s, malaria was endemic through the United States and much of Europe. Insecticides (usually DDT), cheap medications, and civil-engineering projects to reclaim marshy land all contributed to its rollback and eventual eradication (maps of historic US incidence can be found here). But the problem turns out to be a complicated one, because multiple species of Plasmodium parasites infect humans (see here and here), with vastly different consequences.

Additionally, malaria mosquitoes exhibit very different behaviour: some bite inside the house, some outside; some are diurnal and some nocturnal; some are seasonal and some breed year-round. And they can breed in very small amounts of standing water: puddles, not lakes. It’s important as well to note that in some areas of the world people might be exposed to three infectious bites per year, and in others, depending on the season, it could be three per day.

The easiest way to prevent malaria is by preventing mosquito bites, and bednets, sometimes treated with insecticide, are commonly recommended. Unfortunately, they can be unaffordable, they tear, it can be hot to sleep under them, and if they’re not carefully arranged the mosquitoes get in anyway. Insecticide spraying, usually inside and around a house, has been adopted by a number of governments. But this has to be done carefully and frequently, or else the mosquitoes develop resistance to the insecticide; and in any case some mosquitoes may be more prone to biting away from human habitation — for example, when people are farming or gathering firewood.

On the parasite side, quinine has been used against malaria, more or less successfully, for centuries. But because quinine is a natural product and hard to synthesize in the lab, during the Second World War chloroquine came into widespread use. Since parasites had evolved resistance to chloroquine by the 1960s and 1970s, mefloquine became more prevalent; however, mefloquine is both more expensive and responsible for disturbing side-effects, and due to parasite resistance to most drugs when used alone, combination therapies based on artemisinin are now broadly administered.

It’s important to consider cost, efficacy, and kinetics when choosing antimalarials. First, many people at risk of any form of the disease live on $2 or less per day and cannot afford pricey medications; secondly, many of the historically used drugs have lost their effectiveness against parasites due to the acquisition of drug-resistance over decades of frequent use; thirdly, “cutting” medicines is fairly common, so antimalarials may be sold at subtherapeutic doses, which further contributes to the problem of resistance; and lastly, when using a combination therapy, it’s necessary to select the partner drugs carefully, as each will have a different half-life in the blood, which can also lead to parasite drug-resistance acquisition. Additionally, the stress the parasite experiences from exposure to some antimalarial drugs can actually favour the sexual life-cycle stages, enhancing transmission to mosquitoes.

All these factors together have conspired to make this an incredibly tough public-health issue, and yet there’s been huge progress over the past hundred years: first, as the disease was pushed toward the Equator during the 20th century, and more recently, as concerted efforts by regional governments, public-private partnerships, and NGOs collectively managed to reduce overall incidence, and nearly halve mortality, between 2000 and 2013 (see, e.g., the Bill and Melinda Gates Foundation, Roll Back Malaria, World Bank, Medicines for Malaria Venture). This is an issue that will continue to require sustained, and collaborative, effort for many years to come, and both creativity and a multi-pronged approach are imperative. But we should honour the gains that have already been made through multinational coordination — and work to ensure that they persist.

Some additional facts and figures

About half of the global population is at risk of contracting malaria in a given year. It was eradicated from the United States and many European countries only during the 20th century, and is still sporadically endemic in some Mediterranean and central Asian countries, as well as in much of Southeast Asia and Africa and portions of Latin America (http://www.euro.who.int/en/countries/armenia/news/news/2011/04/continued-fall-in-malaria-cases-across-europe).
The economic burden is substantial, particularly in sub-Saharan Africa and Southeast Asia. Studies have tracked lost productivity (one example can be found at http://www.malariajournal.com/content/7/1/166), and have also looked at economic gains apparently resulting from eradication (http://apj.fas.harvard.edu/increased-economic-productivity-after-suppressing-malaria-transmission-in-14-african-countries/).
Resistance to most drugs has been observed; there is no vaccine. Plasmodium parasites practice “immune evasion” and can escape surveillance by the immune system, which has made vaccine development very difficult. Immunity to falciparum malaria typically only comes with repeated childhood exposure and can be lost as an adult.
Malaria vectors are still present in areas where the disease is no longer present. Vacations in the tropics and/or movement of displaced persons can result in the disease gaining purchase in areas from which it had been eliminated.
The hardest work is yet to come. Areas where malaria is currently endemic can often have complex factors at work, including multiple mosquito species, multiple parasite species — perhaps resistant to antimalarials — and migration of infected individuals who subsequently infect mosquitoes and thereby enhance local parasite diversity.