Study shows infant immune systems respond differently to severe COVID-19

Infants hospitalized with severe COVID-19 have significantly different immune responses than adults or older children. The finding comes from scientists at St. Jude Children’s Research Hospital, The Jackson Laboratory for Genomic Medicine, Weill Cornell Medicine, Nationwide Children’s Hospital, Icahn School of Medicine at Mt. Sinai and Yale University.

The researchers established the unique features of hospitalized infants’ immune cells during mild, moderate and severe COVID-19. The study may help identify better ways to protect infants from the disease. It was published today in Nature Communications.

“This is one of the first studies to characterize the immune response in young infants hospitalized with severe COVID-19 with high-resolution,” said co-corresponding author Octavio Ramilo, MD, St. Jude Department of Infectious Diseases chair.

“We found that the infant immune system’s response to SARS-CoV-2 looks nothing like the immune response at any other age, highlighting the need to study infants, specifically, if we want to prevent severe infections and understand the unique features of the infant immune system.”

The collaborators studied immune cells from infants ranging from a few weeks to 16 months old who were hospitalized with mild, moderate or severe disease. They compared those cells to immune cells from healthy infants and a published cohort of adults hospitalized with COVID-19.

Monocytes (a type of white blood cell) from hospitalized infants appeared to have some similar features to those in adults infected with SARS-CoV-2. However, two other major white blood cell types, T and B cells, looked very different than in any other group.

Hospitalized infants had more CD4 T cells. Additionally, both T and B cells were still activated despite being largely naïve, having never encountered an infection. These infants’ T and B cells also expressed the antiviral interferon response, which led to high expression of interferon-stimulated genes at a much higher level than in older children or adults.

Conflicting signals from the infant immune system

Almost all infant immune cells expressed high levels of interferon-stimulated genes. At the same time, when the collaborators tested blood from these infants, they found high levels of inflammation-causing molecules (inflammatory cytokines), which differs from previous observations in infants with mild infection. These findings challenge previous beliefs about infant immune responses to SARS-CoV-2.

“Normally, we think about the interferon and inflammation systems being in balance with each other,” said co-first author M. Asunción Mejías, MD, Ph.D., St. Jude Department of Infectious Diseases. “If one is upregulated, the other is downregulated. But what we found was different. In infants, both systems were upregulated in the same cells, monocytes, which we’ve never seen before in other respiratory viral infections.”

The scientists identified the differences in these infants’ immune responses through single-cell RNA sequencing of white blood cells. RNA is a copy of instructions from DNA that lets cells express genes. By looking at the RNA from individual cells, the researchers found the features unique to infants and compared them by disease severity.

They found more severe disease associated with higher interferon and interferon-stimulated gene expression. High levels of inflammatory cytokines also correlated with more severe disease.

“It’s unclear whether these high levels of interferon, interferon-stimulated genes and inflammatory cytokines are protecting those with severe disease or contributing to it,” Ramilo said. “But they are clearly playing a critical role, which will require further studies.”

Understanding infant antibody response is a field in its infancy

B cells produce specialized molecules called antibodies that target particular parts of viruses, bind to them and stop infections. An infant typically relies on their mother’s antibodies until they are about 6 months old. During the pandemic, the researchers examined whether a mother’s immunity to non-SARS coronaviruses, which cause the common cold, would help protect infants.

“We found that these infants made a strong and robust new antibody response to SARS-CoV-2,” said Mejías. “Their pre-existing maternal antibodies against the endemic coronaviruses did not block infection at all.” The finding was surprising; some infants were as young as just a few weeks old and still created an antibody response to the virus. Infants are typically much older before they begin building such responses for other respiratory viruses.

The children in the study also lacked anti-interferon antibodies, which have been associated with severe COVID-19 in adults, emphasizing that lessons from adult immunity may not translate to infant immune responses.

“We showed that these hospitalized infants responded to SARS-CoV-2, but differently than anyone else,” Ramilo said. “As COVID-19 is now an endemic disease, we need to understand the unique features of the infant immune system better so we can find ways to help these babies through such infections during their first months of life.”