Every two minutes, a child dies of malaria. Most victims live in low- and middle-income countries, and although a vaccine against the parasitic disease is slowly being rolled out, it packs a much smaller protective punch than early tests in European adults predicted.
Scientists noticed long ago that people in low- and middle-income countries tend to respond less robustly to vaccines than do people in wealthier parts of the world, but why this occurs has been a mystery. Now, a new study that closely examines the immune systems of children in Mozambique and Tanzania who received the malaria vaccine RTS,S during its final clinical trial provides some much-needed answers (Sci. Transl. Med. 2020, DOI: 10.1126/scitranslmed.aaw9522).
“We set out to explore why vaccines don’t work as well in African populations,” says Danika Hill, an immunologist at the Babraham Institute in Cambridge, UK. Using blood samples from multiple time points in the clinical trial, Hill and her colleagues found that the immune systems of the African children differed based on their ages, which of the two countries they lived in, and whether they had anemia. When they compared the immune responses of the African children to immune responses of Dutch children the same age, who were part of a different study, they found that the African children’s immune systems tend to develop more quickly.
The RTS,S clinical trial, which ran from 2009 to 2014, tested the vaccine in 6 to 12 month-old infants and in older children, 5 to 17 months of age. Experimenters took multiple blood samples from the children over a 32-month period, including before and after they received their shots. The infants received almost no protection from malaria, while for the older children, the vaccine was more than 30% effective.
Hill and her colleagues first wanted to pinpoint why infants and children had such different responses. They found that the infants’ blood had fewer immune cells that respond to vaccines. Next, they characterized how the children’s immune cells changed during the 32 months of the trial. They compared the changes in the two groups of African children with changes over the same period in Dutch children from a different study. Several immune cell types they looked at were either more prevalent, or increased in number more rapidly, in the African children compared to the Dutch ones. “When we applied algorithms to look at the trajectory of immune development, there seems to be a common way that the immune system developed but the African children seem to get there faster than the Dutch children the same age,” says Hill.
The result was slightly surprising, she says, but can probably be explained by the African children’s likely higher exposures to pathogens. “Our findings show that this failure to respond to vaccines isn’t because children have some sort of global failure in immune system development,” says Hill.
The immune-cell profiles also showed that compared to children from Mozambique, children from Tanzania had fewer B cells, which are needed to produce antibodies. The Tanzanian children, it turned out, were also more likely to have anemia, a paucity of red blood cells often caused by an iron deficiency.
B cells develop their ability to produce antibodies over time by differentiating into cells called plasmablasts. So the researchers grew human B cells in a lab dish and used growth factors to stimulate this differentiation. When they exposed the cells to compounds that aid iron uptake, that process happened much more efficiently. Conversely, when they added compounds that soak up iron, the B cells struggled to differentiate. “To be able to reproduce those defects in cell culture gives you the confidence that it is biologically meaningful,” says Michelle Linterman, also an immunologist at the Babraham Institute, one of the study’s senior investigators.
It’s tempting to conclude that giving kids in resource-poor countries iron supplements before administering the vaccine would help, but unfortunately, parasites like malaria thrive on iron too, and iron supplementation raises people’s susceptibility to infectious diseases. Researchers are looking for ways to boost iron in people without making it available to bugs they might host. Meanwhile, says Hill, knowing what determines the vaccine’s efficacy can help evaluate who it’s best likely to help. For example, the World Health Organization is piloting the vaccine in several African countries, but rather than reporting a single estimate for efficacy, as the RTS,S clinical trial did, researchers should break out the efficacy for each country individually, she says.
“This is a very elegant and very helpful piece of work,” says Gregory Poland, a vaccinologist at the Mayo Clinic in Rochester, Minnesota who wasn’t involved in the study. Identifying specific differences in immune-cell composition points to clues about why different people don’t respond the same way to vaccines. What’s more, he says, it lends support to the idea that a one-size-fits-all approach to vaccines “doesn’t make biological sense.”