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While a substantial proportion of adults infected with SARS-CoV-2 progress to develop severe disease, children rarely manifest respiratory complications. Therefore, understanding differences in the local and systemic response to SARS-CoV-2 infection between children and adults may provide important clues about the pathogenesis of SARS-CoV-2 infection. To address this, we first generated a healthy reference multi-omics single cell data set from children (n=30) in whom we have profiled triple matched samples: nasal and tracheal brushings and PBMCs, where we track the developmental changes for 42 airway and 31 blood cell populations from infancy, through childhood to adolescence. This has revealed the presence of naive B and T lymphocytes in neonates and infants with a unique gene expression signature bearing hallmarks of innate immunity. We then contrast the healthy reference with equivalent data from severe paediatric and adult COVID-19 patients (total n=27), from the same three types of samples: upper and lower airways and blood. We found striking differences: children with COVID-19 as opposed to adults had a higher proportion of innate lymphoid and non-clonally expanded naive T cells in peripheral blood, and a limited interferon-response signature. In the airway epithelium, we found the highest viral load in goblet and ciliated cells and describe a novel inflammatory epithelial cell population. These cells represent a transitional regenerative state between secretory and ciliated cells; they were found in healthy children and were enriched in pediatric and adult COVID-19 patients. Epithelial cells display an antiviral and neutrophil-recruiting gene signature that is weaker in severe paediatric versus adult COVID-19. Our matched blood and airway samples allowed us to study the spatial dynamics of infection. Lastly, we provide a user-friendly interface for this data as a highly granular reference for the study of immune responses in airways and blood in children.

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It is not fully understood why COVID-19 is typically milder in children [1][2][3] . Here, to examine the differences between children and adults in their response to SARS-CoV-2 infection, we analysed paediatric and adult patients with COVID-19 as well as healthy control individuals (total n = 93) using single-cell multi-omic profiling of matched nasal, tracheal, bronchial and blood samples. In the airways of healthy paediatric individuals, we observed cells that were already in an interferon-activated state, which after SARS-CoV-2 infection was further induced especially in airway immune cells. We postulate that higher paediatric innate interferon responses restrict viral replication and disease progression. The systemic response in children was characterized by increases in naive lymphocytes and a depletion of natural killer cells, whereas, in adults, cytotoxic T cells and interferon-stimulated subpopulations were significantly increased. We provide evidence that dendritic cells initiate interferon signalling in early infection, and identify epithelial cell states associated with COVID-19 and age. Our matching nasal and blood data show a strong interferon response in the airways with the induction of systemic interferon-stimulated populations, which were substantially reduced in paediatric patients. Together, we provide several mechanisms that explain the milder clinical syndrome observed in children.SARS-CoV-2 infection in children presents with milder disease severity compared with infection in adults 1,2 . The overall risk of severe COVID-19 in children is even lower than originally believed 3 , with around two deaths per million. The molecular basis of the differences in disease progression between children and adults is not understood and may hold clues for better treatment of severe SARS-CoV-2 infection.SARS-CoV-2 uses a host cell-surface protein, angiotensin-converting enzyme 2 (ACE2), as a receptor for cellular entry 4 . Studies suggested that ACE2 expression is both tissue and age dependent 5,6 , with the highest expression found in nasal epithelium of healthy adults 7 and comparatively lower expression in paediatric upper 8 and lower airways 6,9 . These differences were proposed to contribute to reduced disease severity in children, although recent studies have found no correlation with age or infection 10,11 .During the initial antiviral immune response, interferon (IFN) is important in inhibiting viral replication, contributing to both innate and cell-intrinsic immunity 12,13 . Severe COVID-19 in adults has been linked to an impaired antiviral response in the nasal epithelium and blood [14][15][16] , whereas several other studies highlight the contribution of the IFN response to the pathogenesis 17,18 .

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