SARS-CoV-2 Infection in Children: Revisiting Host–Virus Interactions Through Post-Infection Immune Profiling

Children with COVID-19 typically experience milder symptoms and lower hospitalization rates, though severe cases do occur. Understanding age-related immune responses is crucial for future preparedness. We characterized immune response dynamics to SARS-CoV-2 in 145 samples from 119 pediatric patients (<18 years) with confirmed infection, assessed at four distinct time points: <14 days, 14 days–3 months, 3–6 months, and 6–12 months post-infection. At infection, patients presented increased activated T-cells, higher levels of exhaustion (i.e., PD-1+), lower numbers of unswitched memory B-cells, and increased antibody-secreting cells (ASCs). Both humoral and cellular anti-SARS-CoV-2 responses increased over time (all patients showed measurable responses in the last assessment). Asymptomatic/mildly symptomatic patients (58.6%) showed increased specific cellular responses from infection onwards, along with enriched memory B-cell subsets (but not ASCs), and distinct T-cell activation profiles. Children with severe disease were younger, predominantly boys, displayed altered T/B-cell ratios, and reduced PHA responses when infected. Compared to adolescents, younger children showed lower antibody titers and weaker cellular responses to SARS-CoV-2, possibly underlining the higher prevalence of severe manifestations in younger children. Our study illustrates important age-, gender-, and disease severity-dependent variations in immune responses to SARS-CoV-2, which can be helpful in improving patient management and immunization strategies adjusted to age groups.