Mucosal vaccination in mice provides protection 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 4 and 7/8 ligands with a model antigen, ovalbumin, which provided broad, durable protection in mice for at least 3 months against infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Staphylococcus aureus. In addition, the vaccine protected mice from other viruses (SARS-CoV-2, SARS, SHC014 coronavirus), bacteria (Acinetobacter baumannii), and allergens. Protection was mediated by persistent ovalbumin-specific CD4+ and CD8+ memory T cells that imprinted alveolar macrophages (AMs), enhancing antigen presentation and antiviral immunity. 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.