It's been established that the SARS-CoV-2 virus is not as lethal in children as in adults. But the reason for this difference isn't clear.

Virus-specific neutralizing antibodies have been shown to most consistently confer protective immunity in adults, and antibodies specific to the SARS-CoV-2 spike protein and nucleocapsid protein have been detected in convalescent adult patients. But it is important to define the specific nature of antibody response to SARS-CoV-2 infection in relation to age and clinical disease as a means to improving screening and development of targeted therapies.

"Our study provides an in-depth examination of SARS-CoV-2 antibodies in kids, revealing a stark contrast with adults," said lead author Donna Farber, PhD, an immunologist at Columbia University.

Antibody responses in pediatric patients compared to adult patients

The researchers examined antibody responses in four cohorts of patients seen at New York Presbyterian/Columbia University Irving Medical Center hospital and the Morgan Stanley Children's Hospital of New York from March to June 2020. The cohorts contained 70 individuals, including 19 convalescent plasma donors -- adults who recovered from mild COVID-19 -- 13 adults hospitalized with severe COVID-19, 16 children hospitalized with multisystem inflammatory syndrome (MIS-C), and 31 children who were infected with SARS-CoV-2 but did not develop MIS-C.

Researchers quantified anti-spike and anti-nucleocapsid SARS-CoV-2-specific antibodies for each cohort with indirect enzyme-linked immunosorbent assay (ELISA), including immunoglobulin M (IgM) generated initially in a primary response, IgG in serum (blood circulation), and IgA in mucosal secretions.

Overall, the antibody profile among children was similar, and was distinct from that observed in the adult cohorts. Children exhibited a SARS-CoV-2-specific antibody response that was largely limited to IgG anti-spike antibodies with lower neutralizing activity compared to adult COVID-19 cohorts.

Interestingly, children with different disease severities exhibited similar antibody profiles, while in adult cohorts, those with the most severe disease had higher abundance, types, and neutralizing activity of anti-SARS-CoV-2 antibodies compared to adults who recovered from mild disease.

"In kids, the infectious course is much shorter and probably not as disseminated as in adults," said author Matteo Porotto, PhD, associate professor at Columbia University. "Kids may clear this virus more efficiently than adults and they may not need a strong antibody immune response to get rid of it."

According to the authors, the majority of exposure to pathogens occurs during infancy and childhood, establishing virus-specific memory in adult life. Reduced clinical severity of SARS-CoV-2 infection in children could be due to lower expression of angiotensin-converting enzyme 2 (ACE2) in pediatric airway epithelial cells or could be due to a more robust innate immune response in children.

Furthermore, "children are uniquely adapted to see pathogens for the first time," explained Farber. "That's what their immune system is designed to do. Children have a lot of naive T cells that are able to recognize all sorts of new pathogens, whereas older people depend more on our immunological memories. We're not as able to respond to a new pathogen like children can."

In regard to the lack of antibodies against the nucleocapsid protein in the pediatric cohorts compared to the adult cohorts, Farber explained that this suggests that in children, infection may not spread to other types of cells

"Because children clear the natural virus rapidly, they do not have a widespread infection and they do not need a strong antibody response," Porotto added.

What's next?

While the researchers suggested that the course of SARS-CoV-2 infection in children and adults is different, it's still not known how the children are able to clear the virus more easily -- and what the adult immune system lacks. The researchers are now looking for differences in T-cell response, especially T cells that reside in the lung. They are also investigating delayed innate immune responses in adult patients compared to children.

"There are still all these issues that we have very little information about," Porotto said. "The interaction between the virus and the host is the reason why we see so much diversity in responses to this virus, but we don't understand enough about this virus yet to really determine what leads to severe disease and what leads to mild disease."

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