You’d think that the first-ever vaccine candidate to protect against malaria would be cause for jubilation. But instead, as data on the candidate, known as RTS,S or Mosquirix, have dribbled out over the past couple of years, it has been greeted with considerable head-scratching and some consternation about whether and how to use it.
The problem is that the vaccine, developed by pharmaceutical giant GlaxoSmithKline (GSK) in partnership with the PATH Malaria Vaccine Initiative, doesn’t work all that well. In a large phase III trial, it reduced episodes of malaria by about one-third in young children in sub-Saharan Africa. That’s well under the 50% efficacy expected at the beginning of the trial, and a far cry from the 95% efficacy vaccine makers dream of, leaving scientists and policymakers asking: How good is good enough?
Part of that answer came today, as the European Medicines Agency (EMA) endorsed the vaccine for use in African children 6 weeks to 17 months old. The move is a key first step on the complicated path to potentially rolling out the vaccine in sub-Saharan Africa. Under the fastest scenario, however, introduction will not begin until 2017.
“We are very much thrilled with the outcome, says Moncef Slaoui, the chair of GSK vaccines who for the past 30 years has been working alongside Joe Cohen and others to develop the vaccine. “Child health in Africa will be transformed,” he predicts.
But ask any malaria expert about what to do with RTS,S and they will tell you, “it’s complicated.” There’s no question that the vaccine candidate is a huge achievement: No one has ever developed a vaccine against a parasite, especially one as wily as Plasmodium falciparum, the major cause of malaria in Africa. And malaria is an enormous problem, claiming nearly 600,000 lives a year, mostly children in sub-Saharan Africa. New tools to reduce malaria’s toll are desperately needed.
But at the same time, everyone, including GSK scientists, wants something better from a vaccine. At the end of the multistage RTS,S trial, which overall involved 16,000 children in eight African countries, the vaccine reduced malaria cases 39% in toddlers aged 5 to 17 months and 27% in infants 6 to 12 weeks old. Because the vaccine’s efficacy wanes with time, the trial tested three doses delivered 1 month apart, followed by a booster 18 months later.
The EMA’s “positive scientific opinion,” as it is awkwardly called, essentially concludes that the benefits outweigh the risks of using the vaccine in both age groups. The opinion is not a recommendation for use or a formal approval—that is for countries to decide—but it paves the way for the World Health Organization (WHO) to make a global recommendation on whether and how to use the vaccine. The WHO is expected to issue that recommendation by the end of the year.
The EMA review is part of an arcane regulatory process known as article 58. As a service to poor countries that might not have the scientific expertise, the agency’s Committee for Medicinal Products for Human Use reviewed the scientific evidence—in this case hundreds of thousands of pages—with same rigor as it would in reviewing a drug to be marketed in the European Union.
Next, in its review, WHO will look at such real-world questions as cost-effectiveness, feasibility, and the public-health value of the vaccine compared with other interventions. The outcome could go many ways. For instance, WHO could recommend the vaccine’s use in all African countries affected by malaria or only in areas where transmission is high. It might recommend its use just in toddlers, in which efficacy was higher, or in infants as well.
A second WHO committee will rule on whether the vaccine meets international standards of quality and safety and efficacy.
As with the EMA, WHO’s recommendations are not binding, but resource-poor countries usually follow them. And donors like GAVI, the vaccine alliance, will not pay for the vaccine in poor countries without this recommendation.
Ultimately, it will be up to regulatory agencies in individual countries to decide whether to approve RTS,S. Assuming WHO recommends the vaccine’s use, it will be a “tough decision” for countries with limited resources, says Mary Hamel, an epidemiologist at the U.S. Centers for Disease Control and Prevention and one of the principal investigators. David Kaslow, vice president of product development for PATH, agrees. “It is a bit unusual since the vaccine would be introduced in context of other interventions, which also have costs associated with them,” he says.
If the vaccine does move forward, scientists and policymakers agree, it should be used only as a complement to other tools to fight malaria, such as bed nets and antimalarial drugs, not as a replacement. Nor should financing of the vaccine divert resources from other effective interventions or research, WHO said today in a statement.
The EMA’s opinion is sure to fuel an ongoing debate over whether it is better to wait for a near-perfect malaria vaccine or make the best with what you’ve got. In a BBC commentary, GAVI head Seth Berkley and Mark Dybul, head of The Global Fund, explore the dilemma.“Mosquirix is about 5 to 10 years ahead of any other candidate vaccines,” they write, “and there’s no guarantee any of them will be better.”
“With every vaccine of course you hope for 100% protection,” Slaoui says, and GSK is already working on a second-generation vaccine. But he calls the current vaccine’s protection “substantial.” “If your child has three cases of severe malaria a year instead of six, it will change their lives.”