Our long-term goal is to understand the cellular and molecular basis of immunological memory in humans. We will address this important question in Project 1 by doing a detailed analysis of both humoral and cellular immunity in a longitudinal cohort of over > 700 COVID-19 patients that we have been following for the past three years and will now follow for another five years. These patients were recruited at our two clinical sites located in Atlanta (Emory University) and Seattle (Fred Hutchinson Cancer Center). This combined cohort consists of individuals who were first infected with SARS-CoV-2 and then got the Pfizer or Moderna mRNA vaccine, and some individuals who received the vaccine first and then got infected. Many of these individuals have then gotten booster shots with the vaccine and several of them have also had additional breakthrough infections. During this three-year period of multiple antigen encounters of various combinations of infection and vaccination, we have collected between 5-10 longitudinal blood samples from each patient. We now propose to follow these patients for another five years and will collect 3-4 samples per year from each patient. Thus, we will have 20-30 longitudinal blood samples from each patient over an 8-year period. In addition, in the next five years we will also collect bone marrow aspirates and mucosal samples from a subset of these individuals. The Specific Aims of Project 1 are as follows: Aim 1: To determine the magnitude and durability of humoral and cellular immunity in the entire cohort of > 700 COVID-19 patients over a period of 8 years. Aim 2: To examine the evolution of memory B cell responses and determine the longevity of bone marrow plasma cells. Aim 3. To track differentiation of T cells over time and define the transcriptional and epigenetic signatures of virus specific memory CD8 and CD4 T cells.