�޻���ֱ��

Babies are immature in a lot of ways—but their immune systems aren’t one of them.  

“We’ve always learned that babies are relatively immunosuppressed or are susceptible to infections because their immune systems are immature—it’s one of those things that just becomes kind of dogma, and that you take with a grain of salt,” said , an assistant professor of clinical pediatrics at Weill Cornell Medicine and a pediatric infectious disease specialist and hospital epidemiologist at New York-Presbyterian Komansky Children’s Hospital. “But there's been, over the last decade, a paradigm shift.”  

Researchers are finding that it’s less that the neonatal immune system is a rudimentary version of the adult immune system, and more that it’s just…different. It’s a fine clarifying point with potentially important implications for how we think about early-life immunity, especially in the context of susceptibility to (and prevention of) infection.

Baby Immune Systems Are Fine-Tuned for Infancy

Being born is the most abrupt shift in existence we all experience (rivaled only by our inevitable exit from this thing called life). Neonatal immune defenses at dealing with what it means to be a fresh human, including facing a maelstrom of microbes and the molecular novelty of literally everything in the environment.  

While this is quite a feat, infant immunity is often assessed by the degree to which it falls short of adults: a meek version of something fierce. But this framing can distract from the incredible complexity of the system, and obscure how it functions in the state of life it exists in.

“It's worth considering the evolutionary origin of neonatal immunity,” said , a professor of medical microbiology at the University of Georgia College of Veterinary Medicine who studies interactions between bacteria and the immune system. “An adult might encounter 1 or 2 or 3 new pathogens on a bad day, but every neonate, at the moment of birth, transitions from a near sterile environment in the uterus to our very microbe-rich world. [While] the adult immune system protects against those 1 or 2 pathogens, the role of the neonatal immune system is to mediate this transition.”

Acker agreed. “It’s not that babies have cells that don't function as well [as adults]. Their cells are just regulated differently to do things like be able to have immune tolerance against all these immune antigens they're being exposed to after they're born.” 

Neonatal Immune Cells Are Different From Adults

Take , a cornerstone of the adaptive immune system, as an example. These cells are usually activated when the T cell receptor recognizes a specific microbial component (antigen). Depending on the T cell, it then either destroys host cells infected with the offending microbe or orchestrates a broader immune response to combat it. However, emerging research shows that, in neonates, T cells —a first line of defense. They elicit a quick, broad response that aligns with the need for immediate protection against an onslaught of diverse microbial triggers.

“We have to think ‘What is the use of an adaptive response to infants?’” explained , a Ph.D. student in the Harvill lab, underscoring that the point of adaptive immunity is to gear up for a subsequent infection by a pathogen. Yet, “if you can’t respond to the first infection, what’s the use of being prepared for the second? That’s why infants need these more innate-like factors, rather than putting in the headway for later adaptive functions.”

The general flavor of the T cell response in infants is also than in adults. Indeed, babies have robust regulatory responses that tamp down inflammation, which can be damaging, and ensure tolerance of some microbes—this is, after all, also the time of life when the microbiome is establishing. On the flip side, these responses may blunt the ability of the immune system to deal with pathogens effectively.

And it’s not just T cells that behave differently in the early days of existence—nearly every immune cell does: neutrophils, dendritic cells, B cells, the list goes on. Sedney noted that adults do have some immune cells that share the form and function of those found in infants, they just have different concentrations of them.

But babies also have components of their immune systems that adults simply do not. For instance, from the pregnant parent to infant during gestation and breastfeeding/, are integral to protecting babies against infection. They can also , both positively and negatively (e.g., impeding generation of antibodies by the baby). Whether an infant adequately mounts a response to a pathogen may depend, in part, on the repertoire of antibodies with which they’re working.

Highly Susceptible to Some Infections, Less So to Others

With that in mind, people often think of babies as immunologically fragile and susceptible to lots of infections. This thinking is not without merit; Acker highlighted microbes like respiratory syncytial virus (RSV), Escherichia coli, Group B Streptococcus and enterovirus are especially threatening to neonates.

Sedney, who studies Bordetella pertussis, noted that infants are more at-risk of severe respiratory infections by the bacterium, possibly because it specifically attacks pieces of the neonatal system, or, as suggested by Harvill, because it targets responses that are accentuated/more important in infants relative to adults. In either case, Bordetella is bad news for babies.

However, there are also pathogens that don’t pose a big issue for neonates. A poignant example: pretty well (a surprise to physicians like Acker, who were gearing up for a lot of incredibly sick babies at the onset of the pandemic). Recent studies show that infants and young children produce antibodies against SARS-CoV-2 that can as those of adults. Why? That is still unclear. What is clear is that the neonatal response is nuanced. “[Babies] are much more resilient than people think,” Acker said.

Making Vaccines With Babies in Mind

So, babies are not immunologically little adults—does it matter? When it comes to clinical care, this conceptual frameshift doesn’t change much right now. However, on the research side of the equation, pivoting away from trying to understand neonatal immunity through the lens of adulthood may influence what such clinical care looks like. 

Consider vaccines, the best tools available to prevent severe disease caused by a mickle of microbes. The immaturity of infant immunity is often pegged on the fact that, though babies’ speedy immune defenses are solid, their immune memory—required for effective responses to vaccines and protection from repeated infection—is less refined. The result is diminished responses to vaccinations, and the requirement for more doses with shorter term protection. (Though there are vaccines, such as the Bacillus Calmette–Guérin (BCG) vaccine against Mycobacterium tuberculosis, that babies mount vigorous responses against, further emphasizing the nuance of early-life immune processes).

Meeting neonatal immunity where it’s at, so to speak, could spur development of vaccines that “actually mobilize the immune responses [babies] do have to get protection started as early as possible,” Acker stated.  

"A lot of what has been happening in terms of vaccines for neonates [focuses on] how can we essentially manipulate the immune system to make [the] kind of response that we know is protective in adults,” Sedney said. “But if we think about the neonatal immune system as different from adults, then we're going to get more unique strategies that might be working better.”

(substances in vaccines that enhance the immune response) that work better in babies? How might mechanistic insights shape the timing of vaccine administration? Can scientists harness unique aspects of the neonatal response for preventive purposes? There are already vaccines that leverage the pregnant parent’s response to combat infectious threats (e.g., Pfizer’s induces production of anti-RSV antibodies in pregnant people, who then pass the antibodies to their babies to prevent severe disease). But even the ins and outs about how these vaccines work are somewhat of a mystery. 

“We know that antibodies are transferred from mother to offspring, and that's often assumed to be the whole story,” in part because antibodies are easy to measure, Harvill said. “But while they almost certainly do contribute, we have some good data suggesting that's not the whole story. And so, understanding [how pregnant parents] transfer protection to the offspring is a big black box right now.” 

Different Biology, Same Health Care Woes

Illuminating that and many other black boxes scattered throughout the infant immune system could be a big step for advancing neonatal care. But Acker emphasized that there is more to infection susceptibility than the immune system. Neonatal immune responses may differ from adults, but babies are still subject to the same health care disparities as anyone else. Racial biases, socioeconomic hurdles, insurance roadblocks and language barriers are underlying inequalities in and .  

This is important because it influences how biological research translates into actionable outcomes, and who benefits. It’s great if scientists learn how neonatal T cells work; it’s even better if those insights lead to novel methods for preventing or treating disease. But if, systematically, a baby can’t receive optimal care for their infection, does all that work really make a difference? 

“I think with children we try to equalize [them]. We try to [give them] the same care,” Acker said. Yet, for a slew of reasons, including the fact that infants are not prioritized in clinical trials, they can slip through the cracks. “They’re a vulnerable population in general, just from being kids, and then you add on all the other factors in society.” 

Protecting the tiniest humans from tinier microbes means understanding their immune system for what it is—a complex constellation of responses specifically attuned for the demands of infancy. It means drawing from that system to understand infant susceptibility to infections, including which ones and why, and what to do about it. 

And it also means recognizing that maybe a baby’s immune system isn’t the problem. Maybe adults—the ways we think about immunity, the inequitable health care systems we create—have some work to do.

---

How is immunological memory developed? What are current challenges in the field and proposed advancements to enhance long-lasting immunity to pathogenic infections? Find out in this next article.