The overarching goal of our CCHI application on “Vaccine and Infection Induced Immunity in the Young and Aged” is to address fundamental issues about innate and adaptive immunity in humans to infection and vaccination. Our proposal is focused around a large cohort of > 700 COVID-19 patients that we have been following for the past 3 years and now propose to follow for an additional 5 years during the course of this proposal. These patients were recruited at our two clinical research sites, Emory University (Atlanta, Georgia) and Fred Hutchinson Cancer Center (Seattle, Washington). Our combined cohort of > 700 patients consists of individuals who were first infected with SARS-CoV-2 and then received the mRNA Pfizer or Moderna vaccine, and some individuals who got the vaccine first and were then infected. Several of these individuals then had booster shots and some also had breakthrough infections. During this 3 year period of multiple antigen encounters we have collected on average between 5-10 blood samples from each patient. We now propose to collect 3-4 samples/year from each patient for the next 5 years. The longitudinal assessment of innate, humoral and cellular immunity in this large cohort over an 8 year period with 20-30 time points for each person will provide an extraordinary and unprecedented look at the durability and evolution adaptive and innate immunity following infection and vaccination. These studies will not only provide insight into the underlying mechanisms of innate immunity and long-term immune memory but will also inform how we develop optimal vaccination strategies against SARS-CoV-2 and other emerging viral infections. We have assembled a group of outstanding investigators from five institutions with highly complementary expertise and organized our renewal application along the following Projects and Cores: Project 1: Immune Memory: Drs. Rafi Ahmed and Julie McElrath; Project 2: Innate Immunity: Drs. Bali Pulendran and Donna Farber; Project 3: immune Senescence: Dr. Jorg Goronzy; Core A: Administrative: Dr. Rafi Ahmed; Core B: Genomics Core: Drs. Steve Bosinger and William Greenleaf; Core C: Clinical and Biostatistics: Drs. Sri Edupuganti, Julie McElrath, Max Lau, and Veronika Zarnitsyna. The overall broad Aims of our CCHI program are as follows: Aim 1: Longitudinal analysis of T and B cell responses to SARS-CoV-2. Aim 2: Innate Immunity with focus on functional and epigenetics changes in myeloid cells. Aim 3: Effect of aging on SARS-CoV-2 T cell responses.