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new study of the world’s first malaria vaccine suggests that three doses of the vaccine do not prevent infection in the long term and may cause what’s described as a rebound, with vaccinated children in high-risk areas contracting the illness later.

The research, published Wednesday in the New England Journal of Medicine, reported that when the vaccine is given in three doses, the protection was negligible in the fourth year after immunization.

And after five years, children who got the vaccine contracted malaria at a higher rate than those in the control group who received another inoculation instead — so the vaccine didn’t prevent but only delayed infection. The children in the study were followed for seven years.

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The thinking is not that the vaccine in some way caused the vaccinated children to contract malaria, but rather that it shifted the time at which they were most vulnerable.

The vaccine — called RTS,S — is made by GlaxoSmithKline. Since this study was started, a decision has been taken to add a fourth dose to the vaccine regimen, to stretch out the protection.

Proponents of the vaccine suggested the study’s findings are interesting, but not alarming.

“If you have a vaccine that you know has waning efficacy, you would predict that the age at which you had peak onset of disease will shift out,” explained Dr. David Kaslow, vice president of product development for the PATH Malaria Vaccine Initiative, a program established to spur development of a malaria vaccine.

“So you’re protected while the vaccine is working, and you’re not protected when the vaccine wanes.”

Whether this matters or not is currently an unanswered question. Philip Bejon, the senior author of the study, said it’s not clear if children who contract malaria at age 7, say, are more likely to survive — or get sicker — than if they developed malaria as toddlers.

“Is delaying the age at which most of the malaria occurs going to be good or bad or indifferent? And the answer is, I think, we don’t really know,” said Bejon, an epidemiologist at the KEMRI-Wellcome Trust Research Program in Kilifi, Kenya, where the study was conducted.

It’s also not known if there will be a rebound effect in children who get four doses of the vaccine, but the issue should be studied, Bejon said.

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GlaxoSmithKline and PATH issued a joint statement on the study that did not address the rebound phenomenon.

It did say that an ongoing study of some children immunized with four doses of the vaccine will help to determine how long RTS,S protects when given on that schedule.

The research was supported by PATH, GlaxoSmithKline Biologicals, and Britain’s Wellcome Trust.

Some diseases can only be contracted once in a lifetime; measles is an example. But malaria is different. There are so many strains of the parasites that cause it that people living in places where malaria is found are generally infected multiple times.

Immunity builds up after a while in places where there is a lot of malaria, so it is largely a childhood disease, with children infected a number of times before they start school.

The global burden of disease from malaria is enormous and the quest for an effective vaccine has been a long and difficult one. RTS,S is the first vaccine that protects against a parasite.

But the modest protection it offers and the need for at least four doses has caused concern. Last fall, the World Health Organization’s expert panel on immunizations declined to recommend use of the vaccine, saying more research is needed to see if it could be effectively administered in real-world settings.

The problem: The fourth dose is given at an age when no other childhood vaccines are given, raising questions about whether parents will bring their children back to a clinic for a single shot. As the study published Wednesday reaffirms, without the fourth dose the protection erodes pretty quickly.

“If we can’t get four doses of this vaccine into the children, we’re not going to be using it in the long run,” Dr. Jon Abramson, chair of the WHO’s Strategic Advisory Group of Experts on Immunization said last fall in announcing the group’s recommendation.

“We think we can [get four doses in] but it’s going to be a lot of hard work and it’s going to be a lot of effort to figure out how we can do it.”

Just last week the board of GAVI, the vaccine alliance that provides heavily subsidized vaccines to the world’s poorest countries, announced they would pick up 50 percent of the cost of pilot studies that will explore  how the vaccine could be effectively used. UNITAID, another nongovernmental group, is looking at whether it could raise the funds to meet the rest of the costs.

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