DDT A Symbol Gone Awry

In the 1950s a worldwide campaign to eradicate malaria had as its centerpiece the spraying of houses with DDT (dichlorodiphenyltrichloroethane). In less than two decades, the pesticide enabled many countries to control the disease. In India, for example, deaths from malaria plummeted from 800,000 annually to almost zero for a time.

Then, in 1972, the U.S. government banned DDT for spraying crops—although public health and a few other minor uses were excepted. Rachel Carson's eloquent book Silent Spring, published a decade earlier, is often said to have sparked the ban. Carson meticulously charted the way DDT travels up the food chain in increasing concentrations, killing insects and some animals outright and causing genetic damage in others. DDT became a symbol of the dangers of playing God with nature, and the developed countries, having got rid of malaria within their borders, abandoned the chemical. Most of Europe followed the U.S. in banning the pesticide for agricultural applications in the 1970s.

For sub-Saharan Africa, where malaria still rages, these decisions have meant the loss of a valuable weapon. Most countries there go without DDT not because they have banned it themselves—in fact, it is allowed for public health uses in most areas of the world where malaria is endemic— but because wealthy donor nations and organizations are resistant to funding projects that would spray DDT even in responsible ways.

Many malaria researchers think DDT should be given another look. In addition to being toxic to mosquitoes, they note, it drives the insects off sprayed walls and out of doors before they bite, and it deters their entry in the first place. It is a toxin, irritant and repellent all rolled into one. Moreover, it lasts twice as long as alternatives, and it costs a quarter as much as the next cheapest insecticide.

The chemical's deadly trajectory through the food chain had its roots in massive agricultural spraying (mainly of cotton fields)—not in its much more moderate use inside dwellings to repel mosquitoes. Dusting a 100-hectare cotton field required some 1,100 kilograms of DDT over four weeks.

DDT alone will not save the world from malaria; for instance, spraying houses works only against mosquitoes that bite indoors. Effective drugs for patients already infected are essential, as are other measures to control mosquitoes. But most malaria health professionals support the targeted use of DDT as an important part of the tool kit. —The Editors

1997 1999 2001 2003

Annual maximum

00T spraying begins New drug treatment begins

MALARIA CASES DECLINED dramatically in KwaZulu-Natal when the South African government sprayed dwellings with DDT and later also treated patients with an artemisininbased combination treatment (graph). One of the few African countries wealthy enough to fund its own program, it did not have to rely on aid from donors reluctant to use the chemical. The eaves of a typical African house, such as those in the photograph, provide many points of entry for mosquitoes.

percent were insecticide-treated. A summary of 34 surveys conducted between 1999 and 2004 reached an even more depressing conclusion; a mere 3 percent of African youngsters were protected by insecticidal nets, although reports on the ground now suggest that use is quickly rising.

Insecticide resistance could also undermine nets as a long-term solution: mosquitoes genetically capable of inactivating pyrethroids have now surfaced in several locales, including Kenya and southern Africa, and some anophelines are taking longer to succumb to pyrethroids, a worrisome adaptive behavior known as knockdown resistance. Because precious few new insecticides intended for public health use are in sight (largely because of paltry economic incentives to develop them), one solution is rotating other agricultural insecticides on nets. Decoding the olfactory clues that attract mosquitoes to humans in the first place is another avenue of research that could yield dividends in new repellents. (Ironically, a change in body odor when P. falciparum parasites are present in the blood may also attract mosquito bites; according to a recent report, Kenyan schoolchildren harboring gametocytes—the malaria stage taken up by mosquitoes—drew twice as many bites as their uninfected counterparts.)

How about harnessing the winged creatures themselves to kill malaria parasites? In theory, genetic engineering could quell parasite multiplication before the protozoa ever left the insects' salivary glands. If such insects succeeded in displacing their natural kin in the wild, they could halt the spread of malaria parasites to people. Recently native genes hindering malaria multiplication within Anopheles mosquitoes have been identified, and genetically reengineered strains of several important species are now on the drawing board. Once they are reared in the laboratory, however, releasing these Trojan insects into the real world poses a whole new set of challenges, including ethical ones.

Bottom line: for the time being, old-fashioned, indoor residual spraying with DDT remains a valuable public health tool in many settings in Africa and elsewhere [see box on facing page]. Applied to surfaces, DDT is retained for six months or more. It reduces human-mosquito contact by two key mechanisms— repelling some mosquitoes before they ever enter a dwelling and killing others that perch on treated walls after feeding. A stunning example of its effectiveness surfaced in KwaZulu-Natal in 1999 and 2000. Pyrethroid-resistant A. funestus plus failing drugs had led to the largest number of falciparum cases there since the South African province launched its malaria-control program years ago. Reintroduction of residual spraying of DDT along with new, effective drugs yielded a 91 percent drop in cases within two years.

Treating the Sick

ANTIMOSQU1TO MEASURES alone cannot win the war against malaria—better drugs and health services are also needed for the millions of youngsters and adults who, every year, still walk the malaria tightrope far from med ical care. Some are entrusted to village herbalists and itinerant quacks. Others take pills of unknown manufacture, quality or efficacy (including counterfeits) bought by family members or neighbors from unregulated sources. In Africa, 70 percent of antimalarials come from the

An ancient disease that is both preventable and curable still claims at least one million lives every year.

informal private sector—in other words, small roadside vendors as opposed to licensed clinics or pharmacies.

Despite plummeting efficacy, chloroquine, at pennies per course, remains the top-selling antimalarial pharmaceutical downed by Africans. The next most affordable drug in Africa is sulfadoxine-pyrimethamine, an antibiotic that interferes with folic acid synthesis by the parasite. Unfortunately, P. falciparum strains in Africa and elsewhere are also sidestepping this compound as they acquire sequential mutations that will ultimately render the drug useless.

Given the looming specter of drug resistance, can lessons from other infectious diseases guide future strategies to beef up malaria drug therapy? In recent decades resistant strains of the agents responsible for tuberculosis, leprosy and HIV/AIDS triggered a switch to two- and three-drug regimens, which then helped to forestall further emergence of "superbugs." Now most experts believe that multidrug treatments can also combat drug resistance in falciparum malaria, especially if they include a form of Artemisia annua, a medicinal herb once used as a generic fever remedy in ancient China. Artemisia-derived drugs {collectively termed "artemisinins") beat back malaria parasites more quickly than any other treatment does and also block transmission from humans to mosquitoes. Because of these unequaled advan tages, combining them with other effective antimalarial drugs in an effort to prevent or delay artemisinin resistance makes sense, not just for Africa's but for the entire world's sake. After all, there is no guarantee malaria will not return someday to its former haunts. We know it can victimize global travelers. In recent years P. falciparum-inkcted mosquitoes have even stowed away on international flights, infecting innocent bystanders within a few miles of airports, far from malaria's natural milieu.

Yet there is a hitch to the new combination remedies: their costs—currently 10 to 20 times higher than Africa's more familiar but increasingly impotent malaria drugs—are hugely daunting to most malaria victims and to heavily affected countries. Even if the new cocktails were more modest in price, the global supply of artemisinins is well below needed levels and requires donor dollars to jump-start the 18-month production cycle to grow, harvest and process the plants. Novartis, the first producer formally sanctioned by the WHO to manufacture a co-formulated artemisinin combination treatment (artemether plus lume-fantrine), may not have enough funding and raw material to ship even a portion of the 120 million treatments it once hoped to deliver in 2006.

The good news? Cheaper, synthetic drugs that retain the distinctive chemistry of plant-

based artemisinins (a peroxide bond embedded in a chemical ring) are on the horizon, possibly within five to 10 years. One prototype originating from research done in the late 1990s entered human trials in 2004. Another promising tactic that could bypass botanical extraction or chemical synthesis altogether is splicing A. annua's genes and yeast genes into Escherichia coli, then coaxing pharmaceuticals out of the bacterial brew. The approach was pioneered by researchers at the University of California, Berkeley.

Preventing, as opposed to treating, malaria in highly vulnerable hosts—primarily African children and pregnant women—is also gaining adherents. In the 1960s low-dose antimalarial prophylaxis given to pregnant Nigerians was found, for the first time, to increase their newborns' birthweight. Currently this approach has been superseded by a full course of sulfadoxine-pyrimethamine taken several times during pregnancy, infancy and, increasingly, childhood immunization visits. Right now the recipe works well in reducing infections and anemia, but once resistance truly blankets Africa, the question is, What preventive treatment will replace sulfadoxine-pyrimethamine? Although singledose artemisinins might seem the logical answer at first blush, these agents are not suitable for prevention, because their levels in blood diminish so quickly. And repeated

EBRAHIM SAMBA, who recently retired as the WHO's Regional Director for Africa, still bears delicate hatch marks incised on his cheeks at the age of two, when he was close to death from severe malaria.

dosing of artemisinins in asymptomatic women and children—an untested practice so far—could also yield unsuspected side effects. In an ideal world, prevention equals vaccine.

Where We Stand on Vaccines

THRRK IS NO DOUBT that creating malaria vaccines that deliver long-lasting protection has proved more difficult than scientists first imagined, although progress has occurred over several decades. At the root of the dilemma is malaria's intricate life cycle, which encompasses several stages in mosquitoes and humans; a vaccine effective in killing one stage may not inhibit the growth of another. A second challenge is malaria's complex genetic makeup: of the 5,300 proteins encoded by P. falciparum's genome, fewer than 10 percent trigger protective responses in naturally exposed individuals—the question is, Which ones? On top of that, several arms of the human immune system—antibodies, lymphocytes and the spleen, for starters—must work together to achieve an ideal response to malaria vaccination. Even in healthy people, much less populations already beset with malaria and other diseases, such responses do not always develop.

So far most experimental P. falciparum vaccines have targeted only one of malaria's three biological stages—sporozoite, merozoite or gametocyte [see box on page 54S], although multistage vaccines, which could well prove more effective in the end, are also planned. Some of the earliest insights on attacking sporozoites (the parasite stage usually inoculated into humans through the mosquito's proboscis) came in the 1970s, when investigators at the University of Maryland found that x-ray-weakened falciparum sporozoites protected human volunteers, albeit only briefly. Presumably, the vaccine worked by inducing the immune system to neutralize naturally entering parasites before they escaped an hour later to their next way station, the liver.

The demonstration that antibodies artificially elicited against sporozoites could help fend off malaria prompted further work.

Three decades later, in 2004, efforts bore fruit when a sporozoite vaccine more than halved serious episodes of malaria in 2,000 rural Mozambican children between the ages of one and four, the years when African children are most susceptible to dying from the disease. The formula used in this clinical trial (the most promising to date) included multiple copies of a P. falciparum sporozoite protein fragment fused to a hepatitis B viral protein added for extra potency. Even so, subjects required three separate immunizations, and the period of protection was short (only six months). Realistically, the earliest that an improved version of the vaccine known as RTS,S (or any of its roughly three dozen vaccine brethren currently in clinical development) might come to market is in 10 years, at a final price tag that leaves even Big Pharma gasping for air. Because of the anticipated costs, public-private partnerships such as the Seattle-based Malaria Vaccine Initiative are now helping to fund ongoing trials.

There is just one more thing to keep in mind about malaria vaccines. Even when they do become available—with any luck, sooner rather than later—effective treatments and antimosquito strategies will still be needed. Why? First of all, because rates of protection will never reach anywhere near 100 percent in those who actually receive the vaccines. Other malaria-prone individuals, especially the rural African poor, may not have access to the shots at all. Therefore, at least for the foreseeable future, all preventive and salvage measures must remain in the arsenal.

Investing in Malaria

ONCE AGAIN THE WORLD is Coming to terms with the truth about malaria; the ancient enemy still claims at least one million lives every year while, at the same time, imposing tremendous physical, mental and economic hardships. Given our current tools and even more promising weapons on the horizon, the time has come to fight back.

The past decade has already witnessed significant milestones. In 1998 the WHO and the World Bank established the Roll Back Malaria partnership. In 2000 the G8 named malaria as one of three pandemics they hoped to curb, if not vanquish. The United Nations subsequently created the Global Fund to Fight AIDS, Tuberculosis and Malaria and pledged to halt and reverse the rising tide of malaria within 15 years. In 2005 the World Bank declared a renewed assault on malaria, and President George W. Bush announced a $1.2-billion package to fight malaria in Africa over five years, using insecticide-treated nets, indoor spraying of insecticides and combination drug treatments. More recently, the World Bank has begun looking for ways to subsidize artemisinin combination treatments. As this issue of Scientific American went to press, the Bill and Melinda Gates Foundation announced three grants totaling $258.3 million to support advanced development of a malaria vaccine, new drugs and improved mosquito-control methods.

Despite these positive steps, the dollars at hand are simply not equal to the task. Simultaneously with the announcement from the Gates Foundation, a major new analysis of global malaria research and development funding noted that only $323 million was spent in 2004. This amount falls far short of the projected $3.2 billion a year needed to cut malaria deaths in half by 2010. Perhaps it is time to mobilize not only experts and field-workers but ordinary folk. At roughly $5, the price of a lunch in the U.S. could go a long way toward purchasing an insecticide-treated bed net or a three-day course of artemisinin combination treatment for an African child.

In considering their potential return on investment, readers might also recall a small boy with scars on his cheeks who made it through malaria's minefield, then devoted his adult life to battling disease. Decades from now, how many other children thus spared might accomplish equally wondrous feats? a


What the World Needs Now Is DDT. Tina Rosenberg in New York Times Magazine, pages 38-43; April 11,2004.

Medicines for Malaria Venture; www.mmv.org/

World Health Organization, Roll Back Malaria Department: www.who.lnt/malaria


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