Martins, Catarina GregórioÂngelo-Dias, MiguelMartins, CatarinaChasqueira, Maria de JesusBrito, Maria JoãoÂngelo-Dias, MiguelSilva, Tiago MilheiroMatos, Maria VitóriaChasqueira, Maria-JesusLopes, Maria TeresaCrespo, HélioMata, MarianaBorrego, Luís MiguelPaixão, PauloLopes, Maria TeresaBORREGO, LUIS MIGUELPaixão, Paulo2025-10-102025-10-102025-08-222076-0817PURE: 130617957PURE UUID: 736ff969-6daf-471c-90b0-7be8c9b3bcb5PubMed: 41011738Scopus: 105017388999ORCID: /0000-0003-4708-438X/work/193973893ORCID: /0000-0003-0353-0421/work/193974025ORCID: /0000-0001-9933-4075/work/206216934http://hdl.handle.net/10362/189226Children 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.2444501engHumansCOVID-19/immunologyChildMaleFemaleSARS-CoV-2/immunologyAdolescentChild, PreschoolAntibodies, Viral/bloodT-Lymphocytes/immunologyInfantHost-Pathogen Interactions/immunologyB-Lymphocytes/immunologyImmunity, CellularMemory B Cells/immunologyLymphocyte Activationjournal article10.3390/pathogens14090838