The rapid global spread of SARS-CoV-2 has had a significant impact on the cancer population. SARSCoV-2 infection of hematopoietic stem cell transplant (HSCT) recipients leads to a poor prognosis with a ~68% survival rate. Immune mediated protection is critical to protect the HSCT population. However, there are significant gaps in our understanding of vaccine induced immune responses in the HSCT patient population. This proposed research will greatly advance our understanding of 1) mRNA vaccine driven immune responses in immune compromised subject populations, and 2) the functionality of the SARS-CoV-2 antigen specific T and B cell response in the HSCT population; 3) the role of the adaptive immune response in controlling breakthrough infections. The results of this proposal will have both short and long-term impacts. In the short term we will define a series of critical parameters that could improve the quality of life of HSCT patients during the pandemic. These studies will define the immunogenicity of mRNA SARS-CoV-2 vaccines before and after boosters. In two cohorts we will surveil for asymptomatic and symptomatic SARS-CoV-2 infections and evaluate the level of vaccine immunity close to the time of the breakthrough infection. In the long-term the SARS-CoV-2 pandemic was the 3rd global transmission of a novel coronavirus in the past 20 years. It is likely that there will be outbreaks in the future with currently unknown coronaviruses, and thus it is critical to determine now how high-risk groups respond to vaccination and if they require frequent booster vaccinations or potentially higher vaccine doses. Given the speed and efficacy of the mRNA vaccine platform, it is highly likely that the use of this vaccine platform will be expanded to combat other known pathogens, but also could be used to combat any range of potential emerging viral pathogens. The strength, breadth, and durability of responses to mRNA vaccines needs to be determined in different risk groups in longitudinal cohorts now, in order to prepare for future epidemics/pandemics.