Doctors have dreamed for decades of a vaccine against malaria, which sickens more than 200 million people every year. But a new study warns of a potential pitfall: a malaria vaccine could lead to an even more dangerous parasite.

The paper was published this week in the journal PLOS. Researchers working with the leading candidate vaccine immediately questioned it, saying they've seen no sign of dangerous changes as a result of their work.

The study was performed on mice. Researchers monitored the malaria parasite through several generations, comparing parasites in mice who had been inoculated against malaria with mice those who did not receive vaccinations. In the former group, new malaria infections caused more severe illness, as measured by red blood cell count.

Vicki Barclay, the study's lead author, said it shows a need to track the long-term impact of any malaria vaccine, especially since any such vaccine is expected to be "leaky" - meaning it won't offer complete protection, and the disease will continue to spread, albeit at a slower rate. The fear is that malaria could become more deadly, even as it continues to infect people.

The malaria parasite is a challenging foe because of its complex life cycle and its natural variety. After developing in a female mosquito and being transmitted to a human, the parasite first makes a home in the liver, where it multiplies and then emerges in a different form, attacking red blood cells. There are five different species of malaria that can infect humans, each type with an untold number of variant strains, all competing for survival.

As Barclay explains it, a malaria vaccine might essentially stamp out less virulent strains, allowing more dangerous strains to thrive.

But other experts question whether the findings translate outside the laboratory. Ashley Birkett, director of research and development at the Malaria Vaccine Initiative, said his team is tracking the virulence of malaria parasites as part of a large clinical trial testing a vaccine known as RTS,S. And, said Birkett, "We haven't seen any evidence for this type of effect."

Another scientist, a top malaria researcher at the Centers for Disease Control and Prevention, said a look at malaria's natural evolution is reassuring. Dr. John Barnwell says people in malaria-ridden countries tend to be exposed and develop immunity at a young age. But because there are so many strains, the immunity is never perfect -- just as immunity from a "leaky" vaccine isn't perfect. And yet, says Barnwell, malaria has not evolved to be steadily more virulent.

"This [study] is an artificial way of doing it, but it mimics the way it evolves in the real world," says Barnwell.

RTS,S is the only malaria vaccine to reach the point of widespread testing. According to results published late last year, in a group of 6,000 children, RTS,S cut the number of new malaria cases in half. Birkett says additional results will be published this year, and that he hopes the vaccine could be widely available by 2015.

RTS,S is different from the AMA-1 antigen used in Barclay's research in that it attacks malaria parasites in the liver, rather than attacking as they circulate in the blood. Other experimental vaccines, in earlier stages of testing, are based on the AMA-1 antigen.

Barclay agrees her work is very preliminary. "The message from here is to proceed on all fronts with developing a safe and effective vaccine."