One of COVID-19’s many unsolved puzzles is why a SARS-CoV-2 infection has a vastly different impact on children versus adults. Although many hypotheses have been raised, the different responses of the immune systems seem to be a key component between the two. Now, a new study that compared the immune responses of adults and children with COVID-19 has detected key differences that may contribute to understanding why children usually have milder disease than adults. The findings suggest that the poor outcome in hospitalized adults with COVID-19 compared to children may not be attributable to a failure to generate adaptive immune responses.

The findings, which have important implications for vaccines and drugs being developed to curb COVID-19, are published in Science Translational Medicine in the article, “Immune responses to SARS-CoV-2 infection in hospitalized pediatric and adult patients.”

The study, conducted by researchers at Albert Einstein College of Medicine, Children’s Hospital at Montefiore (CHAM), and Yale University, involved 60 adult COVID-19 patients and 65 pediatric COVID-19 patients (less than 24 years old) hospitalized at CHAM and Montefiore Health System between March 13 and May 17. Twenty of the pediatric patients had multi-system inflammatory syndrome (MIS-C).

The children with COVID-19 fared significantly better than adults; the pediatric patients had a shorter length of stay, decreased requirement for mechanical ventilation, and lower mortality compared to adults. More specifically, 22 adults (37%) required mechanical ventilation compared with only five (8%) of the pediatric patients. In addition, 17 adults (28%) died in the hospital compared with two (3%) of the pediatric patients. No deaths occurred among pediatric patients with MIS-C.

The reasons for the differences in clinical manifestations suggest that age-dependent factors may modulate the anti-viral immune response. The patients’ blood was tested for the presence of several types of immune cells, antibody responses, and cytokines, comparing humoral and cellular immune responses of the patients.

“Our findings suggest that children with COVID-19 do better than adults because their stronger innate immunity protects them against SARS-CoV-2, the novel coronavirus that causes the disease,” said co-senior author Betsy Herold, MD, chief of infectious diseases and vice chair for research in the department of pediatrics at Einstein and CHAM. Kevan C. Herold, MD, the C.N.H. Long professor of immunology and of medicine at Yale School of Medicine, was the other co-senior author on the study.

Compared with adult patients, pediatric COVID-19 patients in the study possessed significantly higher levels of certain cytokines associated with the innate immune response. This suggests that young people’s more robust innate response protects them from developing acute respiratory distress syndrome (ARDS)—the hallmark of severe and often fatal COVID-19 cases.

One cytokine in particular, IL-17A, was found at much higher levels in pediatric patients than in adults. “The high levels of IL-17A that we found in pediatric patients may be important in protecting them against progression of their COVID-19,” said K. Herold.

The authors noted that the serum concentrations of IL-17A and IFN-γ, but not TNF-α or IL-6, were inversely related to age. They wrote that, “Adults mounted a more robust T-cell response to the viral spike protein compared to pediatric patients as evidenced by increased expression of CD25+ on CD4+ T cells and the frequency of IFN-γ+CD4+ T cells.”

Both pediatric and adult COVID-19 patients were found to make antibodies against the spike protein of SARS-CoV-2, which the virus uses to latch onto and infect cells. Those spike-protein antibodies include neutralizing antibodies, which block the coronavirus from infecting cells. Counterintuitively, the researchers found that neutralizing antibody levels in adult COVID-19 patients who died or required mechanical ventilation were higher than in those who recovered—and significantly higher than levels detected in pediatric patients.

“These results suggest that the more severe COVID-19 disease seen in adults is not caused by a failure of their adaptive immunity to mount T-cell or antibody responses,” said K. Herold. “Rather, adult patients respond to coronavirus infection with an over-vigorous adaptive immune response that may promote the inflammation associated with ARDS.”

The findings have important implications for COVID-19 therapies and vaccines. “Our adult COVID-19 patients who fared poorly had high levels of neutralizing antibodies, suggesting that convalescent plasma—which is rich in neutralizing antibodies—may not help adults who have already developed signs of ARDS,” said B. Herold. “By contrast, therapies that boost innate immune responses early in the course of the disease may be especially beneficial.”

As for vaccines, B. Herold noted that most vaccine candidates for protecting against SARS-CoV-2 infection are aimed at boosting neutralizing-antibody levels. “We may want to consider assessing vaccines that promote immunity in other ways, such as by bolstering the innate immune response,” she said.

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