mRNA-LNP vaccines targeting conserved virulence factors elicit protective immunity against lethal Legionella pneumophila infection

This is the authors' abstract. We don't add key points for this paper.

Legionnaires’ disease (LD), caused by the intracellular pathogen Legionella pneumophila , imposes a substantial global health burden, yet no vaccine has been clinically approved. Here, we develop mRNA-LNP vaccines encoding conserved virulence factors Pal, PilE, and FlaA. In BALB/c mice, immunization expands T follicular helper and germinal center B cells, elicits high-titer IgG, and induces potent IFN-γ⁺ Th1-type responses, with no observed systemic toxicity. In a lethal challenge model (2 × 10 8 CFU in susceptible A/J mice), monovalent FlaA-LNP confers superior protection with 100% survival and sterilizing immunity, whereas PilE-LNP is less protective. Following sublethal challenge, spatiotemporal profiling in A/J mice reveals systemic CD8⁺ effector responses. At the pulmonary mucosa, more protective vaccine formulations (Pal-, FlaA-, and MIX-LNP) expand CD4⁺ and CD8⁺ memory T cells; yet within the tissue-resident memory T (TRM) subset, the increase is selectively restricted to the CD8⁺. This CD8⁺ TRM enrichment, together with increased alveolar macrophages and mucosal sIgA responses, correlates with protective efficacy and defines the local immune landscape. In the bone marrow, plasma cell fate is antigen-dependent: FlaA is associated with acute short-lived plasma cell bursts, whereas PilE is required for long-lived plasma cell seeding. Correlation analyses further link the Tfh–GCB axis and local lung microenvironment (including memory T cells, alveolar macrophages, and mucosal sIgA) to protective efficacy. Collectively, these findings demonstrate that mRNA-LNP vaccines orchestrate a multilayered immune defense against L. pneumophila , coupling acute humoral recall, mucosal CD8⁺ TRM establishment, and antigen-dependent plasma cell fate, providing a translatable mechanistic framework for next-generation vaccines. It schematically summarizes antigen selection from Legionella pneumophila, mRNA-LNP vaccine construction, immunization and immune responses, lethal intratracheal challenge protection, and the mechanistic immune landscape in the lung, spleen, and bone marrow