Mucosal vaccination transcends pathogen boundaries to protect from diverse respiratory threats

Traditional vaccines target specific pathogens, limiting their scope against diverse respiratory threats. We describe an intranasal liposomal formulation combining Toll-like receptor (TLR) 4 and 7/8 ligands with ovalbumin that provides broad, durable protection for nearly seven months against such threats. In mice, it protected against viruses (SARS-CoV-2, influenza, SARS, SCH014 coronavirus), bacteria (Staphylococcus aureus, Streptococcus pneumoniae), and allergen. Protection was mediated by persistent ovalbumin-specific CD4⁺ and CD8⁺ lung memory T cells that imprinted alveolar macrophages (AMs) via RANKL, enhancing antigen presentation and antiviral immunity; depletion of AMs, abolished protection, while their transfer restored it. Following infection, vaccinated mice mounted rapid pathogen-specific T-cell and antibody responses and formed ectopic lymphoid structures in the lung. These results reveal a class of “universal vaccines,” against diverse respiratory threats.