The big mystery regarding why COVID spares children still exists, but some emerging explanations suggest that children’s innate immune systems respond faster, potentially reducing their risk of severe respiratory infections.

For the past two years, Bali Pulendran, a professor of microbiology, immunology, and pathology at Stanford University, has been investigating a riddle specific to COVID-19.

He previously stated, “The very young and the very old are the most vulnerable populations for almost every infectious disease.” “However, COVID-19 spares the young.”

Though the puzzle underlying this mystery remains unsolved, solutions are on the horizon.

Children Are Different

Kids aren’t little grownups. They may react to infectious diseases similarly or quite differently, depending on their age.

For COVID-19, children typically have a milder version of the illness.

In an interview, pediatrics professor Dr. Cody Meissner of Dartmouth College’s Geisel School of Medicine remarked, “It’s an intriguing question that no one has fully answered.” “A number of theories have been proposed in an attempt to explain this.”

The main cause is that, in comparison to adults, children’s innate immune systems—often referred to as the first line of defense—respond more quickly. They can establish a strong resistance against respiratory infections faster as a result.

A further explanation could be that children have a higher risk of respiratory infections and that some of their past illnesses have given them some immunity against COVID-19.

Children who are not yet fully developed have anatomical disadvantages when it comes to respiratory illnesses. Due to their smaller airway widths, they have more severe symptoms from mucus buildup or inflammation of the airways.

Additionally, according to immunology researcher Kenneth Rosenthal, Ph.D, they have a reduced lung capacity, which makes them more vulnerable to hypoxia with respiratory infections.

However, it has been discovered that children’s noses have higher concentrations of innate immune cells than adult noses, which can aid in the early removal of viruses.

The co-director of Massachusetts General Hospital’s pulmonary genetics clinic and a pediatric pulmonologist, Dr. Lael Yonker, explained that SARS-CoV-2 targets ACE-2 and TMPRSS, which are expressed more in older persons. Compared to adults, children have fewer of both receptors, which could lower the quantity of viral incursions.

Strong Innate Immunity

Studies have shown that most people with severe COVID-19 typically have an impaired innate immune response, in contrast to children who typically have a quick and strong innate immune response.

The immune system we inherit at birth is known as the innate immune response.

Mr. Rosenthal clarified, “[The immune response is] always present and ready to respond to microbes and triggers on the fly.” On the other hand, an adult’s highly developed adaptive immune system is capable of producing more targeted and learned immunity. But it takes days to activate and responds more slowly.

According to a study published in PLOS One, researchers have found that the COVID-19 vaccine itself causes long-term COVID-19 syndrome.

This is not to suggest that the immune system is not adaptable in children. However, children often have less immunological memory than adults since this sort of immunity is developed by exposure to viruses and other infections.

Immunization is mostly utilized in early childhood to support adaptive immunity.

Researchers found that a deficiency in types 1 and 3 interferons was the most prevalent innate protective impairment in people with severe COVID-19. Research has indicated that the strongest types 1 and 3 interferon responses to COVID-19 are mounted by youngsters and that these responses wane with maturity.

According to Mr. Rosenthal, “a large proportion of adult men prone to more serious COVID have antibodies to interferon.” As a result, even though scientists are unsure of the reason why some individuals develop these antibodies, they are unable to mount the initial innate response.

He continued, saying that the illness spreads unchecked as the immune system tries to contain the widespread infection, which could “lead to problematic outcomes.”

Full-blown inflammatory reactions may result from this.

Additionally, children—especially those in the prepubescent stage—have higher activity levels of natural killer cells, which are innate immune cells that destroy cancer and contaminated cells. Per Mr. Rosenthal, the cell “dissipates in teen years.”

Less Prone to Inflammatory Storm

The inflammatory cytokine storm brought on by elevated cytokine levels in the body is a major risk factor for severe COVID-19.

Immune cells release cytokines during an infection to aid in the activation and synchronization of other immune cells. They are always present in some amount in the body.

Immune cells release more cytokines as a warning when the infection is not controlled by the immune system and the virus multiplies. More immune cells are subsequently triggered by these cytokines, resulting in severe inflammation that may eventually cause organ failure, tissue damage, and even death.

Because adults typically have higher blood levels of cytokines—which are supposed to shield their systems from everyday threats—they are more vulnerable to cytokine storms. According to Mr. Rosenthal, they include tobacco, harmful foods, particles in the air, and specific bacteria that reside in our bodies and on our skin. Inflammatory cytokines are produced “on an everyday, routine basis” by the essential defense reactions.

On the other hand, because they are less exposed to pathogenic and environmental insults, children have lower baseline levels of cytokines. Furthermore, they typically have healthier constitutions, fewer chronic illnesses, and bad habits.

Even in the uncommon event that kids get severe COVID-19, which typically manifests as kids’ multisystem inflammatory syndrome (MIS-C), the majority of kids bounce back fast and don’t have any long-lasting symptoms.

“[Children] were easier to treat than adults. Critical care pulmonologist Dr. Joseph Varon, a clinical medicine professor at the University of Houston, told reporters, “I did not lose a single [pediatric] case, whereas adults, we were losing quite a bit of them.”

The Enigma of Mild COVID in Infants

While children and teenagers’ quick innate immune systems and typically stronger constitutions can account for mild COVID-19 cases, this explanation falls short when it comes to newborns and toddlers.

Mr. Pulendran stated, “It’s one of the great mysteries of human immunology.”

Babies are more prone to infections because they usually have lower constitutions and undeveloped innate and adaptive immune systems at birth. Infants born prematurely are especially more susceptible.

Compared to older children and adults under 50, children under the age of two have a significantly increased risk of dying from respiratory illnesses including influenza and respiratory syncytial virus (RSV).

Generally speaking, Mr. Rosenthal stated that babies “do not have any prior immune history and, therefore, no antibodies or T-cell memory to rapidly respond to the challenge.” Additionally, during birth, they have extremely few innate immune cells. They should have enough innate immune cells by the second month of life to get beyond this weakness.

The immune system fully develops throughout the first seven to eight years of life.

Because they have lower water reserves and greater metabolic rates than adults, dehydration poses a lethal risk to afflicted children and newborns.

To the surprise of researchers, however, infants survived the COVID pandemic relatively unharmed.

“We were desperate to find kids with severe symptoms [for our study],” Mr. Pulendran said. “We asked our Cincinnati Children’s collaborators to please send us samples of kids with severe disease. Try as they might, they couldn’t find samples from kids with severe infection in all the four years they were collecting them.”

It was discovered by Mr. Pulendran’s Stanford University study team that infants could mount strong immune defenses against COVID-19.

Adults who contracted COVID-19 naturally tended to develop quick, but transient, antibodies, with a ten-fold decline in antibody levels within six months. Conversely, the antibody response in infants was slower but more consistent. Throughout the 300-day trial, their antibody levels never decreased, either plateauing or increasing until they finally caught up to adult levels at their peak.

Even after a modest COVID-19 infection, adults tended to exhibit an increase in inflammation-promoting proteins in the blood; neonates did not show this elevation. Blood infections and inflammatory indicators can be serious because they can trigger systemic inflammatory responses.

Rather, Mr. Pulendran said, “We saw plenty of these very inflammation-promoting proteins” in the noses of newborns and young children. Since the nose is a more confined location than blood, having more proteins that promote inflammation can aid in lowering the viral load as it invades.

“The virus may be getting nipped in the bud in the nasal tracts,” Mr. Pulendran said.

“So [children are] activating the immune system in the nose to contain that virus, and then their body is not as reactive, which is a good way to respond to the virus without causing more systemic disease,” Dr. Yonker said.

The question of why this is exclusive to COVID-19 and not other respiratory illnesses like RSV and influenza remains unanswered by experts.

Do Children Have an Advantage Over Adults?

Depending on the age range, children typically have a higher chance of surviving newly discovered viral infections than adults do.

Dr. Meissner clarified, “It’s true for lots of viral infections like measles and chickenpox.” “That’s the reason why, before vaccines were developed, kids would have chickenpox parties.” To ensure that their children would get chickenpox when they were younger—knowing that the disease is more severe if received in adulthood—parents would throw parties and invite uninfected children. We now realize that choosing these parties was a bad idea because immunizations provide a far safer way to develop protective immunity, he said.

The Epstein-Barr virus (EBV), which can induce a crippling illness in adults and teenagers, is an exception to this tendency. However, the most common side effect of EBV infection in youngsters is sore throat.

Mr. Rosenthal did point out that illnesses that elude innate immunity are aided in control by the adult version of the immune system, known as the adaptive immune system.

“Progressing into adulthood, we face tuberculosis, fungi, viral infections, and cancers that require antigen-specific immune control … If there is immune memory after the first exposure, it promotes a rapid protection.”

After puberty, adults typically exhibit a reduced ability to react quickly to new illnesses but retain strong immune responses to infections they have already encountered.

“We’re constantly developing this protective response that serves us down the road, so that is probably part of the trade-off. The biggest problem would be having a brand-new virus out of nowhere that we hadn’t had the chance to really build a response to,” Dr. Yonker said.

According to studies, a person’s immune system is at its peak in terms of functionality just before or around puberty. Following that, the immune system gradually ages, a process known as immunosenescence, which is a decrease in immunity.

“There’s a goldilocks period, or the golden age of the immune system, that is somewhere in between the two extremes of age,” Mr. Pulendran said.

“I’m not so sure that we could be so precise as to say that the immune system is at its peak at puberty, but there’s a middle age somewhere, and I would say it’s at around, maybe 12 or 13, and growing to about 30 or so, in which really the immune system could be described as what you might say is at its peak.”

The thymus, which generates adaptive T cells, tends to atrophy and become less active during immunosenescence.

An increase in innate immune cells that inhibit the immune system is also connected to it.

The impacted immune cells are also adaptive. As one age, their immune memory cells proliferate and provide lifelong defense against diseases previously faced. Nevertheless, when a person is exposed to more recent infections, fewer naive T and B cells remain in reserve for the development of new memory cells.

The immune system ages more quickly in people with chronic illnesses and unhealthy lifestyles. Until about the age of 50, resilience developed throughout childhood steadily diminishes, and at that point, the likelihood of infection and more serious consequences becomes more apparent. Nonetheless, several studies indicate that immunosenescence and inflammation can be avoided with a balanced diet, frequent exercise, and a positive outlook.