SARS-CoV-2 infection displays immense inter-individual clinical variability, ranging from silent infection to lethal disease, to multi-system inflammatory syndrome in children (MIS-C) or in adults (MIS-A) that occur 3-4 weeks after acute infection. The mechanisms underlying such broad phenotypic heterogeneity remain largely unknown. Following the development of COVID-19 pandemic, we have established a collaboration with centers in Italy, Chile, and in the United States that have been inflicted by a severe disease burden. We have obtained biological specimens and de-identified clinical and laboratory data from over 1300 patients that have been hospitalized with acute COVID-19, including both adult and pediatric cases. We have also obtained biological specimens from over 100 children with MIS-C and from pediatric controls. Our lab has played a critical role in the distribution of the biological specimens to a large number of intramural investigators. We have performed studies aimed at better defining the molecular and cellular signatures of immune dysfunction associated with acute COVID-19 and MIS-C and at identifying biomarkers and pre-existing clinical conditions that are predictive of poor outcome. We have sought to characterize immunopathological signatures that distinguish the clinical course of COVID-19 infection in children and in adults. We have also aimed at better defining the inflammatory response associated with MIS-C, identifying possible risk factors associated with this condition, and analyzing the impact of treatment on resolution of the inflammation. We have collected biological samples from patients with various forms of inborn errors of immunity (IEI) and from healthcare workers at various time points before and after administration of COVID-19 vaccines, in the intent to analyze the strength and durability of adaptive immune responses and the incidence and severity of adverse events following vaccine administration. Finally, we have aimed at defining whether some of the risk factors associated with increased risk of serious SARS-CoV-2 infection may also be involved in determining an increased risk of breakthrough infection in individuals who have received the COVID-19 vaccine.