Once again, the malaria parasite has demonstrated that it is a particularly formidable foe. The latest results from a clinical trial testing the leading vaccine candidate against the disease show that the vaccine, called RTS,S, lowers the risk of clinical episodes of malaria by just 31% among babies that receive their first dose between 6 and 12 weeks of age. That is significantly lower than the 56% protection the same vaccine seemed to offer older babies and toddlers in data released—to much fanfare—last year.
The results dampen the hope that the vaccine might be used as part of babies' routine vaccinations in the first months of life, which would have been one of the easiest ways to administer it because the health system infrastructure for giving those vaccines is already in place.
Nevertheless, trial leaders and the vaccine's developers put a positive spin on the results, presented today at the International African Vaccinology Conference in Cape Town and published online by The New England Journal of Medicine. "RTS,S can help," says Salim Abdulla, director of the Ifakara Health Institute in Tanzania, one of the study sites. He notes that the protection offered by the vaccine was on top of that provided by bed nets, which were used by 86% of trial participants. "Efficacy was lower than what we saw last year, but there are many possible explanations. We will continue to explore the complex factors behind the differences," he says.
RTS,S is an engineered protein that combines a protein fragment from Plasmodium falciparum, the malaria parasite, and a protein from the hepatitis B virus aimed at bolstering the body's immune response. The vaccine was invented and developed by GlaxoSmithKline (GSK) Biologicals in Rixensart, Belgium, in partnership with the PATH Malaria Vaccine Initiative, and has been studied for more than 2 decades.
The study, the first ever phase III trial of a malaria vaccine, is still ongoing, and full data and analysis of the results won't be published until late 2014. The final results might help explain the differences between the age groups, Abdulla says. Possible explanations include the younger babies' less-developed immune systems, interference from maternal antibodies that babies carry in their first months of life, and interactions with the other vaccines administered at the same time.
There may also be differences in the vaccine's efficacy in areas with different levels of malaria transmission. An earlier phase II study of RTS,S in infants showed much higher efficacy than the current study, but that was in three sites with moderate malaria transmission, notes Joe Cohen, adviser to the GSK Malaria Team and co-inventor of RTS,S. The phase III trial, which involves 15,460 children at 11 sites in seven sub-Saharan African countries, includes sites where there is much more malaria. Site-specific data won't be available until the end of the trial.
Abdulla and Cohen both say they were encouraged by the vaccine's safety. Although babies developed a mild or moderate fever 31% of the time after receiving the vaccine (compared with a 21% fever rate following the control vaccine against meningococcal disease), the rate of severe side effects was slightly lower than in the control group.
Christopher Plowe, a malaria vaccine expert at the University of Maryland School of Medicine in Baltimore who is not involved in the trial, says that last year's results hinted that efficacy in younger babies would be lower. "This is about what was expected based on the interim analysis," he says. The result "makes it harder to envision adding this vaccine to the [standard vaccination] schedule. … At best we have one more modestly efficacious malaria control tool" that will help in some places under some conditions.
Nicholas White, a malaria expert at Mahidol University in Bangkok, agrees. "It was always going to be an adjunct to other interventions," he says. Whether and how RTS,S might be ultimately used "depends on the cost-effectiveness analysis and donor enthusiasm."
"We'd like to have seen higher efficacy than we've seen" in infants, acknowledges Andrew Witty, CEO of GSK. "It's a little frustrating that we're seeing different protection in different age groups. But that's not surprising, and it's not the first time that we've seen different immunological responses in different patient groups." The company "remains completely committed" to further developing the vaccine, he says. GSK has promised to sell the vaccine at the cost of manufacturing plus 5% that will be reinvested into a fund for research into vaccines against malaria or other neglected tropical diseases.