Clinical manifestations of COVID-19 caused by the new coronavirus SARS-CoV-2 are associated with age 1,2. Adults develop respiratory symptoms, which can progress to acute respiratory distress syndrome (ARDS) in the most severe form, while children are largely spared from respiratory illness but can develop a life-threatening multisystem inflammatory syndrome (MIS-C) 3-5. Here, we show distinct antibody responses in children and adults after SARS-CoV-2 infection. Adult COVID-19 cohorts had anti-spike (S) IgG, IgM and IgA antibodies, as well as anti-nucleocapsid (N) IgG antibody, while children with and without MIS-C had reduced breadth of anti-SARS-CoV-2-specific antibodies, predominantly generating IgG antibodies specific for the S protein but not the N protein. Moreover, children with and without MIS-C had reduced neutralizing activity as compared to both adult COVID-19 cohorts, indicating a reduced protective serological response. These results suggest a distinct infection course and immune response in children independent of whether they develop MIS-C, with implications for developing age-targeted strategies for testing and protecting the population. The clinical manifestations of SARS-CoV-2 infection in children are distinct from adults. Children with COVID-19 rarely exhibit severe respiratory symptoms and often remain asymptomatic 2 , whereas adults experience respiratory symptoms of varying severity; older adults and those with comorbidities such as hypertension and diabetes have substantially higher risks of developing COVID-19-associated ARDS with high mortality 2,6. In children, a rare but severe clinical manifestation of SARS-CoV-2 infection designated MIS-C, exhibits similarities to Kawasaki disease in certain inflammatory features and cardiovascular involvement while generally lacking severe respiratory symptoms 3-5. The nature of the immune response to SARS-CoV-2 in children with different clinical manifestations ranging from asymptomatic to MIS-C relative to the more common respiratory manifestations of COVID-19 in adults is unclear. The generation of virus-specific antibodies that neutralize or block infectivity is the most consistent correlate of protective immunity for multiple infections and vaccines 7,8. Antibodies specific for the major SARS-CoV-2 antigens, including the S protein which binds the cellular receptor for viral entry and the N protein necessary for viral replication, have been detected in actively infected patients and in patients with mild disease who recovered 9-12. Anti-S antibodies, in particular, can exhibit potent neutralizing activity and are currently being pursued as a therapeutic option for infusion into patients during severe disease and for targeted generation in vaccines 13-15. Defining the nature of the antibody response to SARS-CoV-2 infection as a function of age and clinical syndrome can provide essential insights for improved screening and targeted protection for the global population that continues to suffer from this relentless pandemic. In this study, we inves...

Immune response dynamics in coronavirus disease 2019 and their severe manifestations have largely been studied in circulation. Here, we examined the relationship between immune processes in the respiratory tract and circulation through longitudinal phenotypic, transcriptomic, and cytokine profiling of paired airway and blood samples from patients with severe COVID-19 relative to heathy controls. In COVID-19 airways, T cells exhibited activated, tissue-resident, and protective profiles; higher T cell frequencies correlated with survival and younger age. Myeloid cells in COVID-19 airways featured hyperinflammatory signatures, and higher frequencies of these cells correlated with mortality and older age. In COVID-19 blood, aberrant CD163 + monocytes predominated over conventional monocytes, and were found in corresponding airway samples and in damaged alveoli. High levels of myeloid chemoattractants in airways suggest recruitment of these cells through a CCL2-CCR2 chemokine axis. Our findings provide insights into immune processes driving COVID-19 lung pathology with therapeutic implications for targeting inflammation in the respiratory tract.

Graphical Abstract Highlights d High-resolution map of human NK cells shows tissue-driven distribution across ages d Differentiated NK cells predominate in blood, bone marrow, spleen, and lungs d Tissue-resident NK cells exhibit specific adaptations in mucosal and lymphoid sites d Lymph nodes and intestines are reservoirs for precursor and immature NK cells

Adaptive immune responses to SARS-CoV-2 infection have been extensively characterized in blood; however, most functions of protective immunity must be accomplished in tissues. Here, we report from examination of SARS-CoV-2 seropositive organ donors (ages 10 -74) that CD4 + T, CD8 + T, and B cell memory generated in response to infection is present in bone marrow, spleen, lung, and multiple lymph nodes (LNs) for up to 6 months post-infection. Lungs and lung-associated LNs were the most prevalent sites for SARS-CoV-2-specific memory T and B cells, with significant correlations between circulating and tissue-resident memory T and B cells in all sites. We further identified SARS-CoV-2-specific germinal centers in the lung-associated LNs up to 6 months post-infection. SARS-CoV-2-specific follicular helper T cells were also abundant in lung-associated LNs and lungs. Together, the results indicate local tissue coordination of cellular and humoral immune memory against SARS-CoV-2 for site-specific protection against future infectious challenges.