Chang Kyung Kang¹, Hyun Mu Shin^2,3,4,5, Wan Beom Park¹ and Hang-Rae Kim^2,3,4,5,6,*

¹Department of Internal Medicine, Seoul National University College of Medicine, Seoul 03080, Republic of Korea. ²Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Republic of Korea. ³BK21 FOUR Biomedical Science Project, Seoul National University College of Medicine, Seoul 03080, Republic of Korea. ⁴Medical Research Institute, Seoul National University College of Medicine, Seoul 03080, Republic of Korea. ⁵WideRiver Institute of Immunology, Seoul National University, Hongcheon 25159, Republic of Korea. ⁶Department of Anatomy & Cell Biology, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.

^*Corresponding author.

An adequate immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is crucial to not only clear the virus but also prevent tissue immunopathology. Because children generally experience a milder course of coronavirus disease 2019 (COVID-19) than adults, it is important to characterize the immune responses to SARS-CoV-2 in children. In an analysis of 91 children (3–11 years old) and 154 adults (20–71 years old), including 35 and 81 SARS-CoV-2 seropositive participants, respectively, Dowell et al. [1]. showed that COVID-19 convalescent children had more robust humoral immune responses to SARS-CoV-2 and endemic human coronaviruses (hCoVs) than convalescent adults. Notably, antibodies cross-reactive to beta-hCoVs were specific for the S2 domain of the spike protein, which is highly conserved among hCoVs, but not for the S1 domain; these cross-reactive antibodies contribute to the higher SARS-CoV-2-specific titer in children. This finding was emphasized by the lower titers of four hCoV-specific antibodies in seronegative children than in adults. Spike-specific T-cell responses were also higher in children, and even SARS-CoV-2-seronegative children showed prominent cellular immune responses to alpha- and beta-hCoVs. SARS-CoV-2-specific T-cell responses in children showed a differential cytokine response with markedly reduced production of IL-2, suggesting a more highly differentiated functional response in children than in adults. Indeed, at 6 months after primary infection, the majority of spike-specific CD8⁺ T cells in children had an IL-2⁻IFN-γ⁺TNF⁺ phenotype. Moreover, the stronger adaptive response in children was maintained for at least 6 months after COVID-19 and exhibited broad activity against numerous variants of concern.