This study used a multi-omics approach to assess immune responses in infants and young children before, during and after a mild infection with SARS-CoV-2. The authors collected blood and nasal samples each week from a cohort of children in Cincinnati, Ohio, that were aged between 1 and 47 months of age, and they profiled antibody, cytokine and immune cell responses. Spike antibodies emerged 4–5 days after children tested positive for SARS-CoV-2, and although maximum titres were lower than those seen during adult infections, the antibody response persisted for longer in the infants and young children and did not show the early decay that normally occurs in adults. Infants and young children with mild COVID-19 also showed other key distinctions from adults or older children with mild COVID-19. First, they had negligible plasma levels of pro-inflammatory molecules (such as IL-6, OSM, TNF or EN-RAGE) and showed a transient increase in plasma levels of IFNα2 and chemokines involved in myeloid cell recruitment (IL-8, CXCL1, CX3CL1); second, they showed evidence of atypical plasmacytoid dendritic cell and myeloid cell activation; and third, they mounted robust TH17-type responses in the nasal mucosa. The authors suggest that the rapid induction of immunity in the nasal mucosa may contain viral replication to this site and contribute to the generally milder disease seen in infants and young children after SARS-CoV-2 infection.