Multisystem inflammatory syndrome in children (MIS-C) during the COVID-19 pandemic raised a global alert from the Centers for Disease Control and Prevention’s Health Alert Network. The main manifestations of MIS-C in the setting of a severe inflammatory state include fever, diarrhea, shock, and variable presence of rash, conjunctivitis, extremity edema, and mucous membrane changes, and in some cases it progressed to multi-organ failure. The low percentage of children with asymptomatic cases compared with mild illness and moderate illness could be correlated with the rare cases of MIS-C. One potential explanation for the progression to severe MIS-C disease despite the presence of readily detectable anti-SARS-CoV-2 antibodies could be due to potential role of antibody-dependent enhancement (ADE). We reason that the incidence of the ADE phenomenon whereby the pathogen-specific antibodies can promote pathology should be considered in vaccine development against SARS-COV-2.