New Victories in an Old War

By Lori Oliwenstein|Tuesday, June 01, 1993
RELATED TAGS: MALARIA, VACCINES
Malaria kills three times as many people each year as AIDS has killed in 14. But a new drug and a new vaccine offer glimmers of hope.

An estimated 2 million people die of malaria each year. More than 300 million suffer the excruciating cycle of fever, chills, and sweating that comes from being infected by one of the four kinds of malaria-causing Plasmodium parasites, which make their way from the saliva of an infected mosquito into the red blood cells of a human. Since the 1960s the situation has gotten worse rather than better, as the Plasmodium parasites have become increasingly resistant to quinine and related drugs. But now at last there is reason for hope: in recent months researchers have announced the successful testing of a new class of drugs for treating malaria and of a promising new vaccine for preventing it. Both developments have their origin in the Third World, which is for the most part where malaria kills.

The new drugs are actually new only to the West. The Chinese have been using the original source of the drugs, a medicinal herb called qinghao, for thousands of years--first as a cure for hemorrhoids; later as a way to break a fever, including a malarial one. For 20 years now Chinese scientists have known that the antimalarial ingredient in qinghao is an extract they call qinghaosu.

Here in America the plant is called sweet wormwood, or Artemisia annua; it belongs to the same genus as common wormwood, the source of the reputedly poisonous flavoring in absinthe. The antimalarial extract of sweet wormwood is called artemisinin, and it appears to be poisonous only to Plasmodium and a few other microbes.

Although Chinese doctors have administered artemisinin to more than a million people, the extract has yet to gain widespread acceptance as a malaria treatment outside China. This is partly because scientific exchange between China and the rest of the world has been almost nonexistent, and partly because of economics. You need several grams of artemisinin to cure a human being, and the plant doesn’t yield a heck of a lot, explains chemist Gary Posner of Johns Hopkins. It would not be economical, says Posner, to farm enough wormwood to make enough artemisinin to solve the world’s malaria problem.

Artemisinin was synthesized in the lab in 1983, but that achievement, too, had little medical impact. The synthesis requires at least 15 chemical steps, says Posner. That’s too time consuming, too costly, and too labor intensive. It’s not viable for large-scale production. So chemists and physicians have been racing to develop a simpler chemical, one that’s equally effective against malaria but easier to make than artemisinin. Posner has now found several promising candidates. We stripped down the chemical structure of the Chinese drug to its bare bones, and in so doing we simplified it so its synthesis takes only six or seven steps, says Posner.

He and his group targeted the active ingredient in artemisinin: a six-cornered ring called a trioxane, consisting of three carbon atoms and three oxygens. The key part of the trioxane molecule is a link between two adjacent oxygen atoms in the ring. That linkage is called a peroxide linkage, Posner explains. If you have a cut, you put hydrogen peroxide on it--it’s an antiseptic. Peroxides cause oxidation. The thinking is that they operate on malaria-infected cells and somehow cause the oxidation that leads to the destruction of the cells.

But trioxanes on their own are not enough to cure a person of malaria. For one thing, unlike the complete artemisinin molecule, they are chemically unable to pass through a cell’s fatty membrane. So what Posner and his team did is take trioxane rings and hook a series of different appendages on them, in the hope of getting a simple compound that can still sneak into a cell and ambush the parasites within. The researchers created 25 different trioxanes.

The Walter Reed Army Institute of Research in Washington, D.C., tested the compounds by placing them in a test tube with malaria-infected cells. Eight of the synthetic trioxanes turned out to be at least as good as artemisinin at defeating the parasite--and some were much better. Encouraged, the Army tested those eight drugs on malaria-infected mice, and two emerged as bona fide mouse-malaria cures. Tests on monkeys have just been completed: Posner says they, too, confirmed the efficacy of the two drugs.

After a few more years of animal testing, the new drugs should be ready for safety testing in humans. But how long it will be before Posner’s compounds or any other artemisinin derivatives (other research groups are following strategies similar to his) reach the world’s malaria victims may depend on business and politics as well as science. This is not a disease that affects U.S. citizens very much, says Posner. It’s a Third World disease and therefore U.S. industry is not very interested in funding the research.

Indeed, the new vaccine against malaria was developed by researchers in Colombia (although they did build on work originally done in the United States and Europe). The leader of the Colombian group is Manuel Elkin Patarroyo, a doctor at the Immunology Institute of the Hospital San Juan de Dios in Bogotá.

The Colombian vaccine contains bits of synthetic, uninfectious proteins that mimic four different proteins from the surface membrane of Plasmodium falciparum, the species of parasite that causes about 95 percent of all malaria deaths worldwide. One of the four proteins is found on the parasite when it is in its larval stage, the stage at which it is injected into the bloodstream by a mosquito. The other three are from the next developmental stage, during which the parasite actually infects red blood cells.

The theory is that the proteins give the patient’s immune system a first, innocuous look at the enemy, so that it is ready and able to fight when the actual parasite appears. But, says Patarroyo, there are genetically determined differences in people’s immune responses: some people are best able to attack the parasite in its first stage, while others attack the second. Patarroyo’s idea was to cover both bases in the vaccine. I think a big problem that most of us had when we originally tried to develop a vaccine, he says, was working with only one single ‘magic bullet,’ which doesn’t exist.

Patarroyo’s strategy apparently works. He and his colleagues recently announced the results of a clinical trial in which they administered their vaccine to 738 volunteers from La Tola, on the southern Pacific coast of Colombia. When all the data were in, Patarroyo found there were nearly 39 percent fewer cases of falciparum malaria among the vaccine recipients than among a control group. Two groups fared particularly well: there were 77 percent fewer cases of malaria in children between 1 and 4, and 67 percent fewer cases in volunteers over 45 years old.

More recently Patarroyo has completed a second trial on 468 volunteers in Ecuador, with even better results, showing 68 percent fewer cases of malaria among all vaccine recipients. Later this year the Walter Reed institute expects to begin testing the vaccine in Thailand; another trial, sponsored by the World Health Organization, began last January in Tanzania. Since 90 percent of all falciparum malaria deaths (and nearly 90 percent of malaria deaths of any type) occur in sub-Saharan Africa, some researchers regard the Tanzanian trial as the acid test of Patarroyo’s vaccine.

Patarroyo, however, believes he already has all the test results he needs. He thinks it is time to stop the trials and start giving the vaccine to whoever needs it. Although a 39 percent protection rate is not extraordinary for a vaccine, 39 percent of 2 million malaria deaths a year is nearly 800,000 lives a year that might be saved if Patarroyo’s vaccine were universally available--and if it works as well as it appeared to in the trials.
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