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Activation of the innate immune system via pattern recognition receptors (PRRs) is key to generate lasting adaptive immunity. PRRs detect unique chemical patterns associated with invading microorganisms, but whether and how the physical properties of PRR ligands influence the development of the immune response remains unknown. Through the study of fungal mannans, we show that the physical form of PRR ligands dictates the immune response. Soluble mannans are immunosilent in the periphery but elicit a potent pro-inflammatory response in the draining lymph node (dLN). By modulating the physical form of mannans, we developed a formulation that targets both the periphery and the dLN. When combined with viral glycoprotein antigens, this mannan formulation broadens epitope recognition, elicits potent antigen-specific neutralizing antibodies, and confers protection against viral infections of the lung. Thus, the physical properties of microbial ligands determine the outcome of the immune response and can be harnessed for vaccine development. [Display omitted] • Size and solubility of microbial ligands determine the immune response • Fungal mannans are directly drained to the LN to drive cell accrual via interferon release • Tuning mannan physical properties broadens epitope specificity of SARS-CoV-2 anti-Spike antibodies • An adjuvant formulation of mannan/alum induces heterosubtypic immunity against IAV The physical properties of fungal mannans determine their immunological activity, and modulating their physical form improves the adjuvant properties of these immune stimuli when included in vaccine formulations directed against respiratory viruses. [ABSTRACT FROM AUTHOR]