As Scientists Probe the Mystery of How Newborns Develop Immunity, Order Rises from the Chaos


Much about the immune system has long been mysterious to scientists. Its activity is incredibly complicated and varies greatly between individuals; a deeper understanding of how the system works could lead to more and better vaccines, and even to a clearer distinction between health and disease.

Now three studies report finding new patterns amid the apparent chaos—including in the crucial days just after birth, when the immune system faces many threats from the outside world for the first time.

European researchers last year published an analysis of the immune systems of 100 infants—half born prematurely—between one and 12 weeks after birth. And in a study appearing this week in Nature Communications, a global consortium of researchers began laying a baseline for healthy immune system development by examining which genes, proteins and immune cells are active during a newborn’s first seven days. “Massive molecular changes are occurring across the first week of life,” says Ofer Levy, a staff physician and director of the Precision Vaccines program at Boston Children's Hospital, who helped lead the most recent study. “Over 1,000 genes changing, many proteins changing, hundreds of metabolites—we’re talking about pretty radical shifts.”

Both of these studies—and a third that looks at the adult immune system—are part of a growing effort to understand not just the system’s pieces but how they fit together, says Petter Brodin, a pediatric immunologist and associate professor at Karolinska Institute in Stockholm, who was the senior author on last year’s paper. “The immune system is so complex; there are so many moving parts,” Brodin says. “If we focus only on, let’s say, one type of cell or protein, we’re not going to be able to see how the system as a whole is wired, or how it’s regulated and functions in a given patient at a given time.”

Brodin adds he was surprised when his own research indicated babies’ immune systems respond to birth in similar ways, regardless of whether they are born full-term or premature. “Something happens when the child comes out and faces the environment for the very first time,” he says. “There’s a lot of drastic changes happening.” Brodin’s research shows bacteria rapidly colonize newborns’ digestive tracts, skin and lungs—which he says appears to be the “driving force” behind the changes. “We think that’s the trigger that happens after birth, which is the reason all of the children are responding so similarly, because they’re all colonized,” he says. More research could help distinguish normal individual variation and determine how newborns with certain characteristics will fare later in childhood, he notes.

In the study published this week, Levy and the other researchers in the international group compared two blood samples from each of 30 newborns in Gambia in west Africa, validating their findings in another 30 newborns halfway around the world in Papua New Guinea. They were able to get immense amounts of data on each child from only one milliliter of blood, which would not have been possible just a few years ago, says Levy, who is also a professor at Harvard Medical School. Although the newborns showed a lot of variation in measures of gene, immune and metabolic activity, the team was surprised to find “core signatures,” he says, as the babies’ genetic and immune activities changed during the first week after birth. The study begins to set a baseline for immune behavior that will be useful for understanding how premature or sick babies differ from that norm, says Levy, whose team is now studying how vaccines affect this trajectory.

James Wynn, an associate professor at the University of Florida who studies blood infections in newborns, agrees the consortium’s study helps establish such a baseline—“what the road map is during that first week.” Wynn, who was not involved in any of the new studies, says he is eager to see data on even more babies—particularly premature infants like those he treats and studies. “I think this work is foundational for determining a disease state,” he says.

In a third recent study, which looked at the immune system in adulthood, scientists at Stanford University and in Israel have spent more than nine years following activity in the immune systems of 135 adults of various ages. That research, published earlier this month in Nature Medicine, indicates that although every adult’s immune system is different, age-related changes follow along a common trajectory. It is as if everyone is driving to the same location but at different speeds, says Shai Shen-Orr, co-senior author and head of the Systems Immunology and Precision Medicine lab at Technion–Israel Institute of Technology.

Shen-Orr says he and his collaborators have used this information to develop a clinical measure of immune health that can tell patients whether their immune system is functioning appropriately—similar to the way cholesterol levels and blood pressure are used to determine cardiovascular health. The data might also help identify people who will not benefit from flu vaccines, he says, adding it could even potentially serve as a reference point for lifestyle changes or medications intended to slow immunological aging.

Wayne Koff, president and CEO of the Human Vaccines Project (an international nonprofit organization working to decode the human immune system), says all these big-picture investigations of the system are crucial for developing next-generation vaccines. Those that are easy to make have already been made, he says; studies like these, which reveal the detailed workings of the immune system, are essential for expanding the portfolio of diseases that can be prevented or treated. “In the last maybe six to eight years, people have realized that understanding the underlying complexity of the human immune system is really at the core of the next revolution in public health,” he says. “It’s the next frontier of medicine.”

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