Drugs + Mosquitoes = Malaria Vaccine?

Scientists have been working for decades to develop a vaccine against malaria, but the Plasmodium parasite is a formidable foe. Although one promising vaccine has finally reached end-stage clinical trials, it provides only partial protection against the disease, which kills up to one million people a year. Now a team of scientists has come upon what could be a relatively simple alternative: Two antibiotics already in widespread use can act as a sort of malaria vaccine in mice. If the find holds up in humans, it could be an inexpensive and relatively safe tool to help control the disease, they say.

People living in areas where malaria is common develop natural immunity, and several scientists have been trying to mimic this effect by creating a vaccine with whole parasites, either damaged or killed. Although small human trials have shown good results, producing and delivering such a vaccine won’t be cheap. Steffen Borrmann of the Heidelberg University School of Medicine in Germany and the Kenya Medical Research Institute in Kilifi and his colleagues wondered whether administering certain antimalarial drugs to people at high risk of being infected might have a similar effect.

The drugs the scientists had been studying are antibiotics that attack a subunit of the malaria parasite called the apicoplast, which has some similarities with bacteria. Previous studies had shown that the apicoplast-targeting drugs have a delayed-death effect: They allow the parasite to grow and replicate in the liver, where the immune system can develop antibodies against the invaders. But they block the parasite's multiplication in the blood stream, which is where Plasmodium causes malaria symptoms including anemia, high fevers, and convulsions. The researchers wondered whether aggressively treating malaria with such drugs might be a safe way to allow people to develop natural immunity. (The drugs are not yet commonly used against malaria.)

The researchers tested two such antibiotics, clindamycin and azithromycin, which are used against a range of bacterial infections, on a mouse model of malaria. They gave the mice a dose of one of the drugs at the same time as they inoculated them with malaria parasites. The parasites infected the animals' livers, but none of the mice developed symptoms of malaria. A month later, after all traces of the drugs were gone from the animals' blood streams, the animals were still immune to the disease: They showed no symptoms after receiving a dose of parasites that gave control animals cerebral malaria—the most deadly form of the disease. Like the controls, mice that had received just the drug but no parasites in the initial protocol also got sick from the challenge dose of Plasmodium, the team reports online today in Science Translational Medicine.

Azithromycin has an especially safe track record in infants and pregnant women, the two most vulnerable groups, Borrmann notes. He says that a combination of azithromycin and chloroquine (a common malaria drug), currently approved to treat pregnant women in areas at high risk of malaria, would be fairly easy to test in an initial human trial. The idea won't work in all malaria-prone areas, he cautions. A fairly hefty dose of parasites seems to be required to prompt strong immunity, so he says areas where malaria hits hard during a single season would be the best places to try the approach. People could receive a dose of drugs at the beginning of the rainy season, which wouldn't prevent infection but would prevent them from developing malaria symptoms. And the symptom-free infection would allow them to develop immunity for the rest of the malaria season. Although widespread treatment always carries a risk of emerging drug resistance, Borrmann says azithromycin has been used in mass campaigns against trachoma without losing its potency.

The studies support the concept of using natural exposure in combination with malaria-fighting drugs to help people build up protection against disease, says malaria vaccine researcher Robert Sauerwein of the Radboud University Nijmegen Medical Center in the Netherlands. "It leaves the natural route of infection intact, and it may also neutralize immune-evasion strategies used by parasite."