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First malaria vaccine slashes early childhood mortality

Huge analysis of RTS,S in Africa shows it decreased toddler deaths by 13%

In a major analysis in Africa, the first vaccine approved to fight malaria cut deaths among young children by 13% over nearly 4 years, the World Health Organization (WHO) reported last week. The huge evaluation of a pilot rollout of the vaccine, called RTS,S or Mosquirix and made by GlaxoSmithKline, also showed a 22% reduction in severe malaria in kids young enough to receive a three-shot series. Hundreds of thousands of children are born annually in the parts of Ghana, Kenya, and Malawi included in the analysis, for which WHO revealed the final data on 20 October at the annual meeting of the American Society of Tropical Medicine and Hygiene.

“The RTS,S malaria vaccine is already saving lives,” said John Tanko Bawa, director of malaria vaccine implementation at PATH, a nonprofit that develops vaccines and therapies for global health problems. He added, “What we have seen is a considerable impact of a vaccine described as having modest efficacy.” (A late-stage clinical trial delivered lackluster results on the durability of the vaccine’s protection.)

The 13% drop in deaths is so remarkable that “I was surprised I didn’t hear any gasps when it was stated,” joked medical epidemiologist Mary Hamel, who led the WHO pilot program. The mortality decline could translate to tens of thousands of lives saved if RTS,S, which WHO approved for widespread use in 2021, is more broadly deployed: In 2021, malaria killed an estimated 468,000 children under age 5 in sub-Saharan Africa. Seventeen countries in the region have already won approval to receive doses that will start to roll out next year.

“The data speak for themselves,” said Kwaku Poku Asante, a physician and epidemiologist who directs the Kintampo Health Research Centre and who oversaw the analysis in Ghana. “This was a very large, very robust evaluation done in a real-life setting, and you’re seeing this huge impact.”

In clinical trial results published in 2015, RTS,S showed 36.3% efficacy against clinical malaria a median of 4 years after toddlers were vaccinated. In the $70 million pilot, mandated by WHO and launched in 2019, nearly 2 million very young children have been vaccinated in the three countries. As the vaccine rolled out, researchers were tasked with studying its real-world impacts on deaths and severe malaria and determining whether it could be fit into routine childhood vaccination schedules without hurting the administration of other vaccines. WHO also asked the researchers to examine safety signals hinted at in the earlier phase 3 clinical trial.

That study associated vaccination with meningitis, an inflammation of membranes that envelop the brain, and a severe complication of infection known as cerebral malaria. They also found more deaths among girls who received RTS,S than girls who received a comparator vaccine, against rabies.

But earlier data from the pilot rollout, released in 2021, showed that those potential safety issues disappeared when the vaccine was administered to hundreds of thousands more children than in the clinical trials, leading WHO to approve the vaccine that year. Unfortunately, the clinical trial data continue to provide fodder for vaccine opponents, Daniel Kyabayinze, director of public health in Uganda, commented to the presenters at last week’s meeting.

To calculate mortality in the three countries, where death registry statistics are unreliable, the researchers employed tens of thousands of community reporters—more than 14,000 of them in Kenya alone—to conduct household surveys of childhood deaths in 79 areas where the RTS,S vaccine was administered and 79 comparator areas where it was not available.

Researchers then compared the death rates of babies whose age made them eligible to receive three doses of the vaccine with those of young children who were not age-eligible for three doses, in both RTS,S areas and unvaccinated areas. The comparison, covering 46 months, revealed the 13% decline in mortality—excluding accidental deaths—attributed to RTS,S. The researchers used the same method to detect the 22% decline in severe malaria, counting admissions for severe cases of the disease at designated “sentinel” hospitals in RTS,S and comparator areas.

The mortality benefit was documented even in the areas with the lowest RTS,S coverage, notes Matthew Laurens, a malaria vaccine researcher at the University of Maryland School of Medicine. Depending on the area, between 63% and 75% of eligible children got the initial three-dose series of the vaccine, given in the first year of life; 33% to 53% got the fourth dose about 1 year later.

Laurens theorizes that beyond preventing malaria, the RTS,S vaccine may be “training” the immune system in a general way that extends a protective benefit against other infections. For instance, clinical malaria is known to exhaust T cells, he says, and vaccination, by preventing infection, might therefore leave T cells readier to combat other pathogens. Such a general survival benefit has been documented for measles and tuberculosis vaccination. Other leading causes of death in the young children in these areas include pneumonia and diarrhea caused by pathogens including Streptococcus pneumoniae and rotavirus.

Data on the feasibility of the vaccine rollout were also promising: Giving RTS,S to 5-month-olds to 24-month-olds did not hurt the uptake of other childhood vaccines, which had been a concern. And it didn’t cause a decline in bed net use due to a false sense of security.

But some public health leaders still worry that uptake of the vaccine will require trade-offs. “We now have an additional tool, and yet we are still struggling to implement the tools that we [already] have in many countries,” David Walton, U.S. global coordinator for the President’s Malaria Initiative, told the panel that presented the data last week. The cost of adding the roughly $10 per dose vaccine to existing prevention efforts “is formidable for many countries,” he noted. A second malaria vaccine called R-21 won WHO authorization earlier this month and is likely to be available more cheaply and in greater quantities than RTS,S.

The lengthy, expensive RTS,S pilot program came at a cost, Hamel acknowledged. It “really did contribute to a delay in widespread use of the vaccine,” she told the audience. But without it, “I really believe that questions would have lingered” about the vaccine’s safety, effectiveness, and impact—and the feasibility of reaching kids. The pilot program and its critical data, she added, have “forged a pathway for future malaria vaccines.”