Research findings could explain why young kids rarely get very sick from COVID-19

It's not that kids don't get infected. They do. More than 90% of kids age 4 and under in the United States test positive for previous or current infection by SARS-CoV-2, the coronavirus that causes this respiratory infection.

Yet, although kids under 5 represent about 6% of the U.S. population, they account for fewer than 0.1% of COVID-19 deaths in this country.

Researchers are intent on finding out why.

"For almost every infectious disease, the most vulnerable populations are at the extremes of age -- the very young and the very old," said Stanford Medicine professor of microbiology and immunology and of pathology Bali Pulendran, PhD. "But with COVID-19, the young are spared while the old are emphatically not. That's been a mystery."

Possible explanations abound regarding young children's remarkable resilience to SARS-CoV-2. They seem to harbor fewer receptors for SARS-CoV-2 on their cell surfaces. They've had more relatively recent encounters with benign coronaviruses than adults (the latter being less inclined to gum one another's toys in day care settings or sneeze in each other's face), bolstering immunity to newcomers.

There's evidence for these and other hypotheses. But much of the solution to the mystery COVID-19 poses may reside inside little kids' noses.

Serendipity and systems immunology

In 2019, the National Institutes of Health awarded a grant to the Cincinnati Children's Hospital Medical Center, led by pediatrics professor Mary Allen Staat, MD, to investigate immune response to babies' very first exposure to influenza. The idea was to get frequent nasal swabs and blood draws from infants and chart the state of their immune response before, during and after infection.

As the nation's leading biomedical research funding entity, the NIH was well aware of Stanford Medicine's prowess in "systems immunology": the use of genomics, epigenomics, proteomics, metabolomics and pretty much every other "omics" you can think of to learn how genes, cells and those highly complicated organisms called "people" respond to infections. So, the Cincinnati Children's Hospital investigators teamed up with Pulendran, who is co-director of the Stanford Institute for Immunity, Transplantation and Infection and -- along with ITI director Mark Davis, PhD -- a leading practitioner of systems biology.

Then came the pandemic, and the lockdown. In this isolation, flu cases fell off a cliff while COVID-19 began to surge.

The scientists pivoted to a study of COVID-19 in kids. Florian Wimmers, PhD, then a postdoc in Pulendran's lab, and his colleagues got hold of nasal and blood samples collected from 54 infants who'd become infected with SARS-CoV-2 before reaching age 2, and from 27 other children who'd tested negative throughout the observation period. For comparison, the researchers obtained similar samples from several dozen adults.

All infected children in the study were, at most, mildly symptomatic.

"We were desperate to find kids with severe symptoms," 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."

Major findings

In a study led by Pulendran and just published in Cell, he and colleagues at Stanford Medicine and several other institutions discovered telling differences between infants and adults.

In the blood of SARS-CoV-2-infected adults, SARS-specific antibody levels rose quickly to a robust peak, then dropped off precipitously, declining by 10-fold within six months.

Infants' blood-borne antibodies to SARS-CoV-2 were a little slower to spike upward in response to SARS-CoV-2 infection. But in stark contrast to adults, their antibody levels never dropped -- they either plateaued at a high level or kept on rising throughout the 300-day observation period, eventually rivaling those of the adults at peak.

"In no case did we see a decline," Pulendran said. "This was completely unexpected."

The kids' antibodies, he noted, tended to be somewhat narrow spectrum: highly effective against the original invading variant, but providing less protection against other SARS-CoV-2 variants.

Another difference: In the blood of adults with even mild COVID-19 cases, there was a big increase in levels of a number of inflammation-promoting signaling proteins, previously shown to be associated with more-severe symptoms. In infected kids' blood, this increase wasn't seen.

In kids noses, though, it was another story.

"In the mucous membranes of the nasal cavity, we saw plenty of these very inflammation-promoting proteins," Pulendran said. Among them was one called alpha-interferon, which has a noted knack for shutting down viral replication in infected cells.

Also absent in kids' blood, but relatively abundant in the mucous membranes of their noses, was an immune molecule that calls in the thugs: That is, it recruits all-purpose pugnacious immune-cell buddies known as neutrophils to the area.

This big overall dichotomy between what's going on in infected infants' blood versus in their noses indicates to Pulendran that "the virus may be getting nipped in the bud in the nasal tracts," which have a rapid, surprisingly effective immune response to a SARS-CoV-2 infection and deny the virus a launch pad for its spread to the lungs.

Pulendran wants to see if any of this nasal magic extends beyond COVID-19 -- he is now collaborating with the Cincinnati Children's Hospital group on influenza and other viruses. He suspects that his COVID-19 findings may not translate directly to other respiratory infections. Kids, after all, get severe cases of respiratory syncytial virus (RSV) and influenza.

"Each pathogen has its own peculiarities," he said.

But, he added, "If we've indeed identified a source of infants' resilience to COVID-19, we should exploit it."

Pulendran envisions, for example, a nasal spray that could be given every couple of months to stimulate in adults' upper respiratory tracts the same immune-response capabilities that infants routinely have in theirs, and prevent the virus from getting a foothold.

"Can we design a COVID-19 vaccine, or an additive to existing ones, that induces an increase in mucosal immunity in the adult nose, as occurs naturally in infants? We don't know," he said.

"You could say we're in the infancy of this research."

A researcher at the University of Tubingen contributed to the study.

The research was supported by the National Institutes of Health (grants R01 AI048638, U19 AI057266 and U19 AI167903), the Bill and Melinda Gates Foundation, Open Philanthropy, and the Violetta L. Horton and Soffer Endowments.