Malaria is endemic in 107 countries around the world. The parasite infects up to 500 million people annually, and threatens a staggering 40 percent of the world's population.
Credit: The Global Fund/John Rae
If malaria has taught humanity anything during the past 4,000-plus years, it is that there is likely no silver-bullet solution to defeating this mosquito-borne illness. Despite some significant victories against the disease in the Americas and Europe, malaria – recently described by one expert as the “most important parasitic infection in people” – remains and even thrives in places such as sub-Saharan Africa.

Humanity’s fight with malaria is now largely a back-and-forth tussle between technology and nature, a battle between mankind’s scientific ingenuity and the ability of an insect and parasite to resist it. The insect and the parasite have been winning this battle recently, but tools do exist to change that.

Malaria begins with a bite. Not just any bite, but one of 60 species of Anopheles gambiae mosquito infected with one of four species of the Plasmodium parasite. The P. vivax parasite has the greatest reach, occurring throughout the tropics and Asia. It is rarely fatal, however, unlike the more severe P. falciparum.

The P. falciparum parasite causes most of the 1.1 million to 1.3 million global malaria deaths yearly, as noted in the World Health Organization (WHO) World Health Reports 1999-2004. Ninety percent of those deaths happen in Africa, and most of them are of children under age five, whose immune systems have not fully matured. It is not unusual for children of this age to play outside in the morning and die in the afternoon of a P. falciparum infection, making prompt diagnosis and effective treatment a cornerstone of malaria control programmes.

Studies reveal that 350 million to 500 million cases of malaria occur annually. The disease is endemic in 107 countries and territories and threatens nearly 40 percent of the world’s population.

Resistance to the cheapest and most commonly used antimalarials – chloroquine and sulphadoxine-pyrimethanine (SP) – has become more and more common. In fact, WHO reports that the only strains of P. falciparum that remain fully sensitive to the drug are found in Central America north of the Panama Canal and on the island of Hispaniola (Haiti and the Dominican Republic). P. falciparum’s resistance to SP has been detected in the Amazon Basin, throughout most of Southeast Asia and Oceania. SP resistance in Africa varies from as high as 50 percent in East Africa to less than 10 percent in southern Africa.

The life cycle of the parasite

Of the three most important infectious diseases – HIV/AIDS, tuberculosis and malaria – it is the latter that many experts consider the toughest to defeat. A parasite contains much more genetic material – about 5,500 genes – than a virus or a bacterium, allowing it to be nimble in adapting to new drugs. Smallpox or measles, by comparison, have fewer than 30 genes each. The malaria parasite also matures and moves around in the human body in different forms, hiding in existing cells until it is ready to attack. Because it exists in different stages in the human body, stage-specific vaccines would have to be developed to contend with this elusive target.

The parasite reaches its human target because a female anopheline mosquito requires a blood meal to produce its eggs. When an infected female feeds, which is typically at dusk or dawn, it injects five to 20 sporozoites, or malaria seeds. These seeds can live within the salivary glands of female mosquito. Within minutes, the sporozoites migrate into the host’s bloodstream and burrow inside the liver.

Though the malaria seeds can remain dormant for years, they typically multiply rapidly over a period of less than four weeks, and mature into merozoites. When a liver cell is filled to capacity, it splits open, spilling thousands of merozoites into the bloodstream. In 48 to 72 hours, the red blood cells burst, releasing another wave of merozoites in search of still more host cells. It is at this time, during the blood stage of the infection, that the victim begins to suffer headaches, muscle and joint pain, sweat-drenching fevers and chills. The blood stage ends in the death of the human host, unless the victim’s immune system finds a way to control the disease.

Some merozoites ignore the search for host cells and differentiate into reproductive cells with the hope of being ingested by an anopheline mosquito. If this occurs, the parasite’s sex cells find the insect’s gut, where fertilisation takes place. New malaria seeds are produced, which can then travel to the mosquito’s salivary gland, the launching pad for another invasion, completing the cycle.

“We know virtually everything there is to know about this parasite,” said Nabie Bayoh, head of entomology at the Centers for Disease Control-Kenya Medical Research Institute, western Kenya. “It changes rapidly, comes in a variety of different forms and is just plain tricky like the mosquito – or ‘flying syringe’ – that delivers it.”

Best defence is a good offence

The simplest way to avoid malaria is to not get bitten by an infected mosquito. Of course, in some places in sub-Saharan Africa – such as the district of Garki, Nigeria, where studies indicated that bite rates averaged 174 bites per night, or the Kou Valley in Burkina Faso, where people were bitten approximately 158 times per night – trying to avoid the sting of a mosquito can be extremely difficult, if not impossible. Still, by using interventions such as insecticide-treated nets, people can give themselves a fighting chance.

Vector control is about trying to make getting bitten by a malaria-carrying mosquito as unlikely as possible. This type of control focuses either on the adult mosquito or on its aquatic stage, where it exists as larvae. The most effective weapons to keep the adult mosquito in check include long-lasting, insecticide-treated bed nets; indoor residual spray, especially DDT (dichloro-diphenyl-trichloroethane); and improvements to house design. For dealing with the insect’s aquatic stage, fish with an appetite for larvae and other types of environmental management, such as drainage of breeding sites, have proven useful. Experts stress that whatever combination of controls is employed it ought to be based on extensive behavioural knowledge of the local vectors.


Under the WHO’s 2005 malaria control guide, indoor spraying of DDT has proven to be an effective, if controversial, method in fighting the disease.
Credit: The Global Fund/John Rae
“I remember being at a conference recently where we were discussing malaria prevention, and during this meeting, a man stood up and declared, ‘Nothing has happened since DDT,’” Bayoh said. “And in a sense, it’s true. It remains the most effective and cheapest instrument in the malaria control toolbox. … The only question is, Can countries like Kenya or Angola or Uganda control it? Can they be trusted to keep it outside of their agricultural sector?”

WHO’s 2005 malaria control guide recommended DDT for vector control, provided it was used only for indoor spraying and proven to be effective. DDT use must also meet WHO Pesticide Evaluation Scheme (WHOPES) product specifications, and the necessary safety precautions must be followed in use and disposal.

WHO also recognised several alternatives to DDT for indoor spraying, but none were less expensive or more effective. Although the 2004 Stockholm Convention on Persistent Organic Pollutants bans agricultural use of DDT worldwide because of its harmful effects on the environment, the convention grants exemptions for such public health purposes as killing malaria-infected mosquitoes.

Turning to bed nets, the United Nations Children’s Fund (UNICEF) predicted that as many as 500,000 children could be saved every year if all children under age five in Africa slept under insecticide-treated bed nets (ITNs). Apart from the colossal challenge of widespread distribution, the problem with bed nets and their sustainable use is the need to re-treat them with insecticide roughly every six months. Long-lasting insecticide-treated nets, the price of which has recently dropped from about US $23 to $6, circumvent this obstacle. These nets last for four or five years and can be washed up to 20 times before requiring a re-treatment.

Another problem with insecticide-treated nets – regardless of how long they remain treated – is a growing resistance by mosquitoes to pyrethroids, the chemicals the nets are laced with. One response being investigated to counter this emerging resistance is to use mixtures or mosaics of insecticides on nets. As many experts have pointed out, however, this approach would make re-treatment of nets problematic.

A new weapon being developed to combat malaria in infants is intermittent preventative treatment (IPTi), which has shown strong results in preliminary trials. IPTi involves giving a course of antimalarials to children during their first year of life. Early studies in Tanzania found IPTi reduced malaria and anaemia in the first year of life by up to 60 percent. The use of this treatment in pregnancy has been a popular tool of policy makers for years and is recommended by WHO in regions of stable (moderate to intense) transmission. For complex reasons, pregnant women, especially during their first pregnancy, have reduced immunity to malaria. An IPTi consortium has been established – its costs are underwritten by a $28 million commitment from the Bill and Melinda Gates Foundation – to hasten the testing of this new preventative measure for children. The consortium will have collected enough information to make policy recommendations by 2006.

The shrinking antimalarial arsenal

There are three main categories of drugs to treat malaria. Antifolates interfere with the parasite’s ability to produce folic acid, a nutrient necessary to keep its metabolic engine running. Sulphadoxine-pyrimethanine is the best known within this category. Aryl aminoalcohol compounds, such as chloroquine and quinine, destroy the asexual form of malaria by transforming its meal, red blood cells, into a parasitic poison. Finally, there are artemisinin and its derivatives, including artemether and artesunate. This class of antimalarial, which has long been a component of traditional Chinese medicine, also turns red blood cells into poisonous food for the parasite. A key difference is that these drugs transform the parasite’s food to poison more effectively, resulting in a rapid clearance of the disease from the bloodstream.

Since 2001, WHO has recommended combination therapies involving two drugs that have independent modes of action and different biochemical targets in the parasite. With no clinical evidence yet of resistance to artemisinin derivatives, many experts hope artemisinin-based combination therapies (ACTs) involving some of the drugs listed above will improve efficacy and prolong the medicines’ usable lifespan.

As effective as ACTs are – extensive tests have proven they are more than 90 percent effective – they do have a number of drawbacks. A course of treatment can cost as much as $2.40, which is at least 10 times more expensive than other antimalarials. Because artemisinin is isolated from a plant, Artemisia annua, it takes up to 18 months to get from seed to pill. This has resulted not only in delays and shortages of the drug but in making it a much more costly venture to scale-up production.

One project aimed at addressing these problems is an attempt to engineer an artificial artemisinin. OneWorld Heath, a California-based nonprofit pharmaceutical company, is using technology developed at the University of California, Berkeley (which granted royalty-free licenses to the company) to create the drug. With a $42 million grant from the Bill and Melinda Gates Foundation, OneWorld Health over the next five years will use synthetic biology technology to try to lower the price from $2.40 to $0.24 per treatment.

In the meantime, counterfeit ACTs, a consequence of their high cost, threaten to undermine not only the OneWorld Health effort, but also the very effectiveness of artemisinin itself. Paul Newton of Oxford University has discovered a thriving counterfeit ACT trade in Southeast Asia, with a disturbing twist. Instead of just starch and chalk as part of the bogus medicine, some fraudulent treatments also contain a small amount of artemisinin. It is surmised this is done to fool simple dye tests used to prove the medicine’s authenticity. By diluting the treatment so there is not enough present to cure, Newton and others fear a resistant strain of the parasite could soon emerge.

"This would be a disaster for malaria control globally,” Newton has said in a number of publications. "We may have malaria that could not be treated in any affordable way."

Working to help avoid such a disaster, the Medicines for Malaria Venture (MMV) has set the goal of registering at least one new effective and affordable drug before 2010. An optimistic J Carl Craft, MMV’s chief scientific officer, has said he expects to have one or two new combination drugs by 2007 and as many as three or four by 2010 to “meet any change in resistance patterns.”

Vaccines

An effective vaccine against malaria has been described by researchers as nothing short of the Holy Grail. The pursuit of such a vaccine has been underway for decades. The first glimmer of hope came in 1973, when the first vaccination against malaria was reported. Although it was achieved by obviously impractical means – a subject became immune only after being bitten about 1,000 times by irradiated malaria-infected mosquitoes – it appeared to illustrate that a vaccine wasn’t impossible. Since that painful exhibition, however, malaria vaccines have rarely progressed to the point of human trials – until recently.

Approximately 40 malaria vaccines are now in clinical trials, according to WHO. Some 45 are in preclinical development, and about 20 are at the research stage. These vaccines can be divided into four types and targeting the parasite at different stages of its life cycle: pre-erythrocyte vaccines, which target the liver stage; blood-stage vaccines, which seek to mimic the natural immunity (something that is still not well understood) of those who survive long-term malaria exposure; vaccines that block parasite transmission to mosquitoes; and antidisease agents that reduce the effect of parasite toxins.

Observers have pointed to a combination of factors to explain this spike in vaccine development. First, there has been a general boost in funding for malaria vaccine research – to which the November 2005 Gates Foundation grant of $107 million to pharmaceutical giant GlaxoSmithKline (GSK) attests. Second, organisations such as the Malaria Vaccine Initiative (MVI) are increasingly using their funding to encourage public-private partnerships, thereby increasing the number of small biotechnology companies willing to enter this market. Finally, technological strides made in the field of genetics, combined with a greater understanding of the structure and behaviour of proteins, have improved vaccine design.

Of the four types of malaria vaccines, those focusing on the liver stage of the infection have shown the most promise, in particular RTS,S/AS02A. Most of the grant to GSK is directed towards the ongoing testing of this “breakthrough” vaccine and its licensing. Trials of RTS,S/AS02A in 2,022 Mozambican children between the ages of one and four showed the vaccine’s efficacy to be 45 percent against infection and 30 percent against mild or non-life-threatening episodes of the disease. It also reduced the number of severe malaria cases by 58 percent after six months. Researchers then followed 1,422 of these children for another 12 months and found clinical malaria episodes were reduced by 35 percent and severe malaria cases by 49 percent. With results such as these coming 18 months after administering the vaccine, investigators concluded in a November 2005 article in the Lancet medical journal: “With sustained funding and improved international partnerships, the first two decades of this century are likely to witness vaccines being part of the armoury against malaria in use throughout the endemic areas of Africa.” This vaccine, Mosquirix, is expected to enter phase-three trials – the last trials before licensing – in late 2007 or early 2008.

A lack of investment

In the summer of 2005, the Wellcome Trust and the Gates Foundation sponsored a Malaria Vaccine Technology Roadmap meeting, to which they invited more than 180 experts from 100 organisations. The upshot of the meeting was two commitments: First, the attendees vowed to have a vaccine – with more than 50 percent efficacy against severe disease and longevity of more than one year – on the market by 2015. Second, they promised a vaccine that is 80 percent effective against clinical disease and lasts more than four years by 2025.

These goals are predicated, in part, on what the RTS,S/AS02A researchers described as “sustained funding and improved international partnerships”. None of the researchers for this feature considered vaccines a “silver bullet” to the problem of malaria. They all saw it as being one important device in a toolbox of malaria controls that included bed nets, indoor spraying, environmental management and drugs. Almost all were convinced that given the malaria controls already available significant gains could be made in the fight against the disease. Richard Feachem, executive director of the Global Fund to Fight AIDS, Tuberculosis and Malaria, has said that he is convinced that the Millennium Development Goals (MDG) target of halting and reversing the incidence of malaria may be the only MDG actually achievable by 2015.


There is an international concern about the lack of malaria experts in Africa. Many observers believe that without proper funding, and adequate facilities, the best researchers will continue to leave the continent.
Credit: Stephenie Hollyman/WHO
Despite the $258.3 million grant in November 2005 from the Gates Foundation, however, experts are concerned that malaria research and development is not receiving enough funding to ensure the MDG will be met. A report published at almost the same time that Microsoft Corp. chairman Bill Gates was announcing his generous donation indicated that only $323 million had been spent on malaria research and development in 2004. This represented approximately 0.3 percent of the total health research and development investment for all diseases worldwide, according to the report. Meanwhile, the study added, malaria accounts for 3 percent of all years of productive life lost to disease.

By contrast, diabetes receives approximately 1.6 percent of total money spent on medical research, while it accounts for 1.1 percent of all productive years of life lost to disease. In other words, diabetes’s burden to society is about one-third of that of malaria, but it gets nearly six times more money for research and development.

Experts are also concerned about the dearth of malaria researchers in Africa. In 1999, there were only 752 trained malaria researchers in sub-Saharan Africa, according to the Multilateral Initiative on Malaria (MIM). By contrast, 1,000 African malaria researchers attended a MIM conference in Cameroon in 2005. Andreas Heddini, secretariat coordinator for MIM, insisted, however, that many more were needed. He also said that to keep researchers in Africa long-term funding and adequate facilities are required.

Without these improvements, many observers feared the best and the brightest researchers would leave the continent, taking vital knowledge and experience with them. “As we see more and more drugs and vaccines that need to be tested in African populations, the presence of well-trained African scientists could become the critical factor in their success or failure,” said Ogobara Doumbo, director of the Malaria Research and Training Centre at the University of Bamako in Mali.

“There’s no doubt this is a very wily beast,” said Brian Greenwood of the London School of Hygiene and Tropical Medicine. “The mosquito and the parasite have illustrated time and time again that they have no intention of giving up without a fight.”

Greenwood has spent almost 40 years on the frontline in the war against malaria, which is long enough to know that there are still battles to be won.

“Given what we know of the mosquito and the parasite, it is going to take a sophisticated response to control this disease. We shouldn’t expect a vaccine or a drug to appear and solve all our problems. Neither is spraying DDT or putting up a bed net going to always be the right prevention. We need, in each place we confront malaria, to carefully think through how we use these tools. This disease has had a long time to evolve and adapt into something quite complex, and our response must be equally complex if we are ever to win this fight.”
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