Summary SARS-CoV-2 vaccines have been developed in record time and are now widely used in many different countries around the globe. Project 1 will focus on characterizing immune signatures associated with SARS-CoV-2 immunization using different vaccine types. In Aim 1 we will leverage existing biospecimen collected before and after vaccination with mRNA-based or adenoviral vector-based vaccines to investigate the durability and breadth of vaccine-induced antibody responses and to determine how early innate immune profiles influence humoral and cell-mediated adaptive immunity following SARS-CoV-2 vaccination. In Aim 2 we will characterize the immune responses specific for break-through infections, despite vaccination with in-depth cellular characterization of selected cases experiencing severe COVID-19. In Aim 3 we will also determine the immune responses in vaccinated individuals who get infected and in individuals experiencing vaccine-associated side effects and reactogenicity. Lastly, in Aim 4, the observations made in human cohorts will be validated in the human primary tonsillar explant model system, by treating these histocultures (HC) ex vivo with the different vaccine types, which will allow us to identify the cells that take up the vaccine preparations as well as those critical for mounting efficient immune defenses. For all these studies, specimens will be facilitated by the Clinical Core and with the assistance of the Immune Phenotyping Core and the Genomics Core, all data generated will be analyzed by the Data Management and Dissemination Core. Integrated analyses of data from different types of specimens using different techniques will be also performed by the Data Management and Analysis Core, which will identify unique signatures for each vaccine platform. Collectively, these studies will contribute to defining the biological correlates of vaccine induced immune protection in the context of SARS-CoV-2 immunization.