OVERALL COMPONENT SUMMARY Our LJI CCHI was first funded in April of 2019 and has been highly impactful in human immunology research in the past < 4 years, particularly in the areas of COVID and COVID vaccines. Crotty and Sette published the first major paper on virus-specific T cell and antibody responses in COVID cases ( > 3,000 citations) and went on to collaboratively publish several more of the most influential T cell, B cell, and immune memory papers on COVID and COVID vaccines. The adaptive immune system is important for control of most viral infections. The three fundamental components of the adaptive immune system are B cells (the source of antibodies), CD4+ T cells, and CD8+ T cells. The armamentarium of B cells, CD4+ T cells, and CD8+ T cells has differing roles in different viral infections, and in vaccines, and thus it has been critical to directly study adaptive immunity to SARS2 (SARS2) to understand COVID. The COVID pandemic has been a historic disaster, with over 1 million American deaths and millions of deaths and billions of infections around the world, counterweighted by the exceptionally efficient development of COVID vaccines which had remarkable efficacy and have saved over 15 million lives in less than two years. In 2023 COVID remains a major American public health problem and global health problem, with COVID being the #3 cause of death in the USA in 2022, and in the USA there were over 1.6 million confirmed new cases of COVID in the month of January 2023 alone. Improvements in controlling COVID remain somewhat impaired by our limited understanding of immune memory and upper airways immunity to SARS2. The overarching focus connecting the three Projects in this LJI CCHI renewal proposal is immune memory, with emphasis on COVID, highlighted by three overall LJI CCHI themes: (1) understanding immune memory in humans from blood samples, rich in complexities; (2) understanding human upper airways T and B cell biology and memory; and (3) COVID immunobiology, including breakthrough infections, differences between COVID vaccines, and immunity relatedness to other respiratory viral infections of humans. These three themes are explored in depth in Projects 1-3 and the Clinical Core.