The public health world has waited for the results for more than a year. After a half-billion dollars in R&D, would the front-runner malaria vaccine protect the top-priority targets: young infants?
The results are disappointing. The vaccine called RTS,S for its various molecular components reduced infants' risk of malaria by about a third.
To be precise, malaria was 31 percent less frequent among 3,200 infants between one and five months old who got the vaccine compared to controls. The risk of severe malaria was 37 percent lower. The infants got three vaccine shots over three months.
The news was announced Friday at a meeting in South Africa and published online by the New England Journal of Medicine.
It was a letdown after the first results from the largest malaria vaccine trial involving nearly 16,000 children in seven African countries. A year ago, researchers announced the vaccine lowered malaria incidence by 55 percent among children aged five to 17 months. The vaccine reduced their incidence of severe malaria by 47 percent.
Malaria experts hoped the efficacy would be as high in young infants. The World Health Organization's goal is a vaccine effective enough to be added to the Expanded Immunization Program for infants.
"The main issue from WHO was: Should we add this to the infant regimen?" Dr. Johanna Daily of Albert Einstein College of Medicine said in an interview with Shots. "And for this vaccine the answer is probably no.
"That's disappointing, but parasites are very good at avoiding our immune system," Daily says, "and (the malaria) parasite resides in our blood where all our immune cells and blood proteins are. So it has gotten particularly good at staying under the radar."
"Everybody would have hoped for that number to be higher" than 31 percent, Laoui told Shots.
But he still has a glass-half-full view of the results.
"This is the second demonstration of a significant effect of the vaccine," he says.
He points out the vaccine reduced the incidence of malaria from 900 cases for every 1,000 infants (among those in a control group) to 640 cases.
GSK has invested $300 million in the RTS,S vaccine, and Laoui says the company expects to spend another $200 million to get the vaccine licensed. He says the company will file for licensure with the European Medicines Agency within the next few months if it has the support of partners such as the Bill and Melinda Gates Foundation.
The main Gates-supported sponsor, the PATH Malaria Vaccine Initiative, also seems undeterred.
"Malaria is so prevalent in these African kids," Dr. David Kaslow of the MVI told Shots, "that even a modest protection translates into large public health impact, just given the sheer numbers. So (the vaccine) will reduce disease and it will save lives."
More than 200 million people get malaria each year, according to the WHO, and 655,000 people die from it. Most of the burden is in sub-Saharan Africa.
Still Kaslow says he can't predict whether RTS,S will ever be widely deployed.
"Sitting with the data we have in hand, I can't answer that question," he says. "The honest answer is, we won't know until 2014."
Between now and then, RTS,S researchers will try to figure out why infants have a less robust immune response to the vaccine.
It could be one or more of several factors. Infants' immune systems are immature and less responsive to infections. Anti-malaria antibodies in their mothers' blood may interfere with infants' ability to make their own antibodies in response to the vaccine. Perhaps the administration of other infant vaccines interferes with their ability to make antibodies to malaria antigens in the vaccine.
Investigators don't know how long-lasting the vaccine's protection is, and how much difference a booster shot would make.
Beyond that, researchers want to investigate whether the vaccine's efficacy varies depending on the prevalence of malaria where they live.
Slaoui hypothesizes that the vaccine may be less effective among infants who live in areas where they are more likely to be bitten by malaria-infected mosquitoes.
"One would rationally expect when you're getting bitten three times a day by an infected mosquito, the chance that one of these would break through (the vaccine's protection) would be higher than if you have one bite per week or one per day," Slaoui says.
There was a wide range of malaria prevalence among the 11 African sites where the vaccine was tested. But so far the researchers haven't parsed vaccine efficacy by the different sites.
That could have important implications for decisions about how or whether to deploy the vaccine. An effective-enough vaccine might tip the balance in areas where malaria has been suppressed over the past 10 years by heavy investments in insecticide-treated bed nets, indoor spraying, and use of effective anti-malaria drugs.
Dr. John Lusingu helped test the vaccine in a district in Tanzania that used to be a high-prevalence area and now is low-to-moderate. He's disappointed the vaccine didn't lower malaria by at least half in infants. But he thinks it could still prevent malaria's high fevers, seizures, anemia and death in a lot of African children.
"Being a father from sub-Saharan Africa, I have witnessed my own children suffer from several episodes of malaria," Lusingu told Shots. "So I would highly encourage that this vaccine should be incorporated into other existing tools to control malaria."
That will be the subject of intense debate over the new few years, says Dr. Richard Feachem, director of the global health group at the University of California San Francisco.
"Because the efficacy is disappointing and there are still some questions about the duration of its protection, those will be difficult discussions," Feachem told Shots.
The best childhood vaccines are 90 percent protective. But many argue that the perfect shouldn't be the enemy of the good-enough.
"A clear failure is a clear failure, and a 90 percent efficacy is, you know, a glass of champagne," Feachem says. "But this lies in the middle because there are so many uncertainties."
Whatever the ultimate fate of the RTS,S vaccine or the 30 other malaria vaccines in the pipeline Feachem says the results increase the urgency to develop new, better insecticides against malaria-infected mosquitoes, and new classes of drugs to cure those who get infected and circumvent the parasites' ability to evade the best current drugs.