Beyond the blood: Tissue-resident immunity shapes SARS-CoV-2 vaccine antibody responses.

Infections and vaccinations elicit coordinated humoral and cellular adaptive immune responses that together provide protection. In addition to antibodies, pathogen-specific memory T and B cells persist in blood and tissues, but it remains unclear how their composition and spatial distribution relate to serum antibody titers, the most common correlate of vaccine-induced protection. Understanding these relationships is essential for predicting vaccine efficacy and optimizing immunization strategies. We analyzed tissues from 58 adult human organ donors vaccinated against SARS-CoV-2, including individuals with and without prior infection. Using multivariate imputation, dimensionality reduction, and correlation, regression, and causal analyses, we identified immune signatures linking memory B cell, CD4 T cell, and CD8 T cell subsets in spleen, lung, and lung-draining lymph nodes with antibody titers and neutralizing activity. Our analyses indicate that humoral immunity is driven primarily by virus-specific B cells and CD4 T cells in lymphoid tissues rather than blood, whereas tissue-localized CD8 T cell responses, although correlated with antibody levels, develop independently. These findings demonstrate that cross-sectional immune profiling across multiple tissues recapitulates established immunological principles and reveal that serum antibody responses emerge from coordinated cellular immune responses distributed throughout the body.