Nov 9, 2012 (CIDRAP News) – The latest trial of the world's first malaria vaccine showed it was only modestly beneficial in African infants, a somewhat disappointing finding after an earlier part of the study showed that it halved cases in older babies.
Researchers found that the vaccine reduced the risk of clinical malaria by 31% and the risk of severe malaria by 26% in babies who were 6 to 12 weeks old when they received their first dose of the vaccine. The latest findings, part of a phase 3 trial that enrolled 15,000 children at 11 centers in seven African countries, appear today in an early online report from the New England Journal of Medicine.
Though global health groups and countries where malaria is endemic have made some headway against the disease in recent years, in 2010 it still accounted for about 216 million infections and 655,000 deaths, according to published estimates. A vaccine would provide a new tool against malaria, especially in African children, who carry the biggest burden of deaths.
The RTS,S malaria candidate vaccine, under development since 1992, contains an AS01 adjuvant and is given in three doses. The vaccine targets the circumsporozoite protein, which paves the way for liver invasion, the parasite's first step in infecting human hosts. The study was sponsored by the vaccine's maker, GlaxoSmithKline (GSK), and funded by GSK and the Program for Appropriate Technology in Health (PATH) Malaria Vaccine Initiative through a grant from the Bill and Melinda Gates Foundation.
In the latest phase of the trial, researchers assessed the efficacy of the vaccine in 6,537 children ages 6 to 12 weeks and compared them with a control group that received a meningococcal vaccine. The two groups received the vaccine along with their standard childhood vaccines.
The researchers explored the vaccine's efficacy against lab-confirmed malaria 12 months after vaccination. They also looked at efficacy against severe malaria, as well as the vaccine's safety and immunogenicity profiles. Parents and guardians were asked to seek care for children in the event of any type of illness so that clinicians could track the incidence of malaria. The adults were also asked to report adverse events in the children.
The group found that the efficacy of the vaccine was 31% against clinical malaria and 26% against severe malaria over the 12 months that followed the third vaccine dose. The researchers said the vaccine provided modest protection when given with the other childhood vaccines.
Investigators noted that insecticide-treated bed nets were used by 86% of the participants,
In an earlier phase of the trial at the same clinics last year, the group found that the vaccine was more effective in children ages 5 to 17 months, with 56% efficacy against clinical malaria and 47% efficacy against severe disease.
The authors wrote that the lower efficacy in the younger group could reflect age-related differences in immune response to the vaccine. They suggested several possible factors: coadministration with other routine vaccines, an inhibitory effect of maternal anti-circumsporozoite antibodies, lack of priming with hepatitis B vaccine or Plasmodium falciparum infection, or the infant's immature immune system.
They also noted that phase 2 trials in infants showed higher vaccine efficacy than the current phase 3 trial, and vowed to do further site-specific analyses to explore if high malaria transmission at some of the sites played any role in the lower vaccine efficacy.
Serious adverse events occurred with a similar frequency in the treatment and the control groups.
Dr Salim Abdulla, a principal investigator from the Ifakara Health Institute in Tanzania, said in a EurekAlert press release that the lower efficacy surprised the research group. "It makes us even more eager to gather and analyze more data from the trial to determine what factors might influence efficacy against malaria and to better understand the potential of RTS,S in our battle against this devastating disease," he said.
"We were also glad to see that the study indicated that RTS,S could be administered to young infants along with standard childhood vaccines and that side effects were similar to what we would see with those vaccines," Abdulla said.
David Kaslow, MD, director of the PATH Malaria Vaccine Initiative, said in the press release that determining what role the vaccine might play in Africa will depend on analysis of additional data. "Success in developing malaria vaccines depends on many factors: at the top of the list are partnerships and robust evidence, coupled with an understanding that different combinations of tools to fight malaria will be appropriate in different settings in malaria-endemic countries," he said.
In an editorial in the same issue of NEJM, Johanna Daily, MD, of the division of infectious diseases at Albert Einstein College of Medicine in Bronx, NY, wrote that developing a malaria vaccine is challenging for several reasons, including the uncertain effects of partial protection from natural infection in malaria-endemic areas.
A key question is why some babies were protected while others were not, she wrote. Researchers should sort out which vaccine-elicited immune responses afforded protection, as has been done with other vaccines, such as the one against yellow fever. "Recent studies leveraging comprehensive immune analysis to inform disease and immune-response models in malaria could also inform the development of malaria vaccines," Daily wrote.
Though the trial results suggest the vaccine isn't ready for routine use in infants, it showed promising protection in a subset of children and should serve as a springboard for finding host responses that correlate with protection, she said. "The results of this immunization trial suggest that a malaria vaccine is possible, but a more detailed understanding of effective host responses will be necessary."
The RTS,S Clinical Trials Partnership. A phase 3 trial of RTS, S/AS01 malaria vaccine in African infants. N Engl J Med 2012 Nov 9 [Abstract]
Daily JP. Malaria vaccine trials—beyond efficacy endpoints, editorial. N Engl J Med 2012 Nov 9 [Extract]
Nov 9 EurekAlert press release
Oct 18, 2011, CIDRAP News story "Study: Malaria vaccine halves cases in young kids"