Mucosal vaccination in mice provides protection from diverse respiratory threats.
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| Title: | Mucosal vaccination in mice provides protection from diverse respiratory threats. |
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| Authors: | Zhang, Haibo (AUTHOR), Floyd, Katharine (AUTHOR), Fang, Zhuoqing (AUTHOR), Hoffmann, Filipe Araujo (AUTHOR), Lee, Audrey (AUTHOR), Froggatt, Heather Marie (AUTHOR), Bharj, Gurpreet (AUTHOR), Xie, Xia (AUTHOR), Eppler, Haleigh B. (AUTHOR), Santagata, Jordan Mariah (AUTHOR), Wang, Yanli (AUTHOR), Hu, Mengyun (AUTHOR), Fox, Christopher B. (AUTHOR), Arunachalam, Prabhu S. (AUTHOR), Baric, Ralph (AUTHOR), Suthar, Mehul S. (AUTHOR), Pulendran, Bali (AUTHOR) |
| Source: | Science. 5/21/2026, Vol. 392 Issue 6800, p1-16. 16p. |
| Subjects: | Vaccination, Alveolar macrophages, Intranasal administration, Immunologic memory, Epigenetics, Immunity, Vaccines, Toll-like receptor agonists |
| Abstract: | 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. Editor's summary: A vaccine that could provide protection against multiple pathogens would be invaluable, particularly during pandemics in which knowledge of the causative pathogen is limited. Zhang et al. found that a nasal vaccine designed to stimulate innate immune cells and T cells provided protection against both viral and bacterial lung infections in mice. Broad protection was dependent on alveolar macrophages, and their vaccine-induced enhanced functions were lost if T cells were depleted. Because macrophages can inhibit viruses and bacteria through a variety of mechanisms, the vaccine promoting their preparedness conferred broad protective function. The T cells stimulated by the vaccine trained the macrophages to be ready to respond to infection, a process that did not require the T cells to have specificity toward a particular pathogen. —Sarah H. Ross INTRODUCTION: Respiratory viruses, bacteria, and allergens are major threats to global health and economic stability. Current vaccines are highly pathogen-specific and generally fail to protect against antigenically divergent or emerging respiratory threats, such as newly evolving coronaviruses or influenza variants. Although some vaccines, including the tuberculosis Bacille Calmette-Guérin (BCG) vaccine, can enhance immunity to unrelated pathogens, these effects are variable and typically modest, and in experimental models they require intravenous immunization—an invasive route that is impractical for immunization campaigns in humans. Developing a mucosal vaccine that elicits durable, pathogen-agnostic protection would transform pandemic preparedness and respiratory disease prevention. RATIONALE: We previously found that intravenous administration of BCG in mice confers broad protection against unrelated respiratory viruses, including coronaviruses and influenza, through a mechanism involving crosstalk between lung T cells and innate immune cells. Based on these findings, we proposed the concept of integrated organ immunity—the coordinated action of adaptive and innate immune cells within an organ that provides broad, durable protection. Building on this framework, we hypothesized that mucosal vaccination could similarly activate integrated organ immunity within the lung to confer long-lasting, pathogen-agnostic protection. To test this idea, we designed a liposomal vaccine formulated with two clinically evaluated toll-like receptor (TLR) agonists—glucopyranosyl lipid adjuvant (GLA) (GLA) (TLR4) and 3M-052 (TLR7/8)—combined with an antigen that could be delivered intranasally. RESULTS: Intranasal vaccination of mice with GLA-3M-052-LS + ovalbumin protein conferred potent protection against diverse respiratory challenges, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), SHC014 coronavirus, SARS-CoV MA15, Staphylococcus aureus, Acinetobacter baumannii, and house dust mite–induced allergic asthma, for at least 3 months. Vaccination generated long-lasting, antigen-specific CD4⁺ and CD8⁺ circulating and tissue-resident memory T cells. CD4 and CD8 T cells were essential for epigenetic changes that imprinted alveolar macrophages (AMs) into a state of persistently increased innate activation, antiviral defenses, and improved antigen uptake and presentation. Multiomic analyses revealed durable epigenetic remodeling of AMs, with enhanced accessibility in genes linked to antigen presentation, phagocytosis, and interferon (INF) signaling. Protection was lost after CD4⁺/CD8⁺ T cell blockade or macrophage depletion showing that vaccine-trained macrophages were essential for protection. T cell–derived receptor activator of nuclear factor kappa-Β ligand (RANKL) is involved in reprogramming, while blockade of CD40L, IFN-γ, or tumor necrosis factor α (TNF-α) had no effect. Although vaccination greatly reduced pathogen burden, it did not induce sterilizing immunity. Upon low-level challenge, vaccinated lungs rapidly formed tertiary lymphoid structures and mounted accelerated local T and B cell responses, limiting inflammation and preserving lung integrity. CONCLUSION: This study defines a clinically translatable mucosal vaccine platform that induces durable, antigen-agnostic protection against respiratory viruses, bacteria, and allergens. The mechanism involves antigen-specific T cells that imprint alveolar macrophages through epigenetic reprogramming, establishing integrated organ immunity in the lungs. This strategy provides a blueprint for universal mucosal vaccines capable of broad respiratory protection and rapid deployment against future pandemics. Design principles of a pathogen-agnostic mucosal vaccine.: Intranasal vaccination with a TLR-based liposomal formulation generates tissue-resident and circulating memory T cells which reprogram alveolar macrophages. These trained macrophages exhibit sustained innate activation, stronger antiviral defenses, and enhanced antigen uptake and presentation, underpinned by durable epigenetic remodeling. After vaccination, local immune responses and ectopic lymphoid structures rapidly form in the lung upon pathogen exposure. [ABSTRACT FROM AUTHOR] |
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| Database: | Psychology and Behavioral Sciences Collection |
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