Lower infection rates and milder clinical course of COVID-19 have been reported in children. In this preprint, the authors hypothesize that this protection could originate from cross-protective immunity following prior infections by seasonal human coronaviruses (HCoVs). The authors measured antibody responses to SARS-CoV-2 in 739 pauci- or asymptomatic children as well as 36 children with suspected multisystem inflammatory syndrome (MIS); in a subset of 187 patients, they also tested the presence of antibodies to the four HCoVs: HKU1, OC43, 229E and NL63. Their data did not show significant differences in antibody levels to HCoV antigens between SARS-CoV-2 seropositive and seronegative patients, regardless of MIS. Together, this study suggests that antibody responses raised against seasonal HCoVs do not confer protection from SARS-CoV-2 and associated MIS in children.