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Highly effective vaccines elicit specific, robust, and durable adaptive immune responses. To advance informed vaccine design, it is critical that we understand the cellular dynamics underlying responses to different antigen formats. Here, we sought to understand how antigen-specific B and T cells were activated and participated in adaptive immune responses within the mucosal site. Using a human tonsil organoid model, we tracked the differentiation and kinetics of the adaptive immune response to influenza vaccine and virus modalities. Each antigen format elicited distinct B and T cell responses, including differences in their magnitude, diversity, phenotype, function, and breadth. These differences culminated in substantial changes in the corresponding antibody response. A major source of antigen format-related variability was the ability to recruit naive vs. memory B and T cells to the response. These findings have important implications for vaccine design and the generation of protective immune responses in the upper respiratory tract.
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•Used tonsil organoids to compare influenza vaccine formats within an individual•Transcriptional fate of Ag-specific B cells is affected by vaccine format•Type I IFNs mediate some but not all of the vaccine-format-specific differences•Inactivated flu vaccine depends on pre-existing memory cells
Understanding the cellular dynamics underlying responses to different antigen formats is critical for rational vaccine design. Using a human immune organoid model, Kastenschmidt et al. evaluate the effect of influenza vaccine modalities on adaptive immunity and reveal key differences in the magnitude, breadth, and quality of B cell, T cell, and antibody responses.