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Pulmonary mRNA-LNP vaccines for rapid and durable protection against bacterial infection
Anqi Wei1, Yu Miao1, Zhou Yuan1
1Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai, PR China.
Abstract:
Pulmonary bacterial infections remain a major clinical challenge. Although vaccination reduces infection rates and mortality, the vulnerable post-vaccination immunity gap can still result in infection and vaccine failure. In addition, effective vaccines are unavailable for many clinically important bacterial pathogens. Here, we report a pulmonary mRNA-lipid nanoparticle (mRNA-LNP) vaccine incorporating an ionizable lipid engineered for localized high-level expression, which elicits both rapid and durable protection against bacterial lung infections in female mice, effectively bridging this critical window of vulnerability. Intratracheal delivery of mRNA-LNP rapidly primes lung neutrophils and macrophages into a transcriptionally pre-activated state, enhancing their phagocytic activity and enabling rapid, antigen-independent bacterial clearance during the early post-vaccination period (approximately 1-7 days). Subsequently, vaccination induces potent antigen-specific adaptive responses, conferring sustained protection against both laboratory and clinical drug-resistant Pseudomonas aeruginosa strains. Single-cell transcriptomics and immune profiling reveal coordinated activation of innate and adaptive immune programs. This dual-phase immune response exemplifies a paradigm-shifting vaccine design that integrates innate and adaptive immunity to confer both immediate and long-term protection. Our findings establish a mechanistic basis for rapid antibacterial defense and highlight pulmonary mRNA-LNP vaccination as a promising strategy for combating respiratory infections.
Insights
A new pulmonary mRNA-lipid nanoparticle (mRNA-LNP) vaccine provides rapid and lasting protection against bacterial lung infections in mice. This innovative vaccine bridges the post-vaccination immunity gap, offering a promising strategy for respiratory infections.
Area of Science:
- Immunology
- Vaccinology
- Respiratory Medicine
Background:
- Pulmonary bacterial infections pose significant clinical challenges.
- Existing vaccines have limitations, including post-vaccination immunity gaps and unavailability for many pathogens.
- There is a critical need for vaccines that provide rapid and durable protection against respiratory bacterial infections.
Purpose of the Study:
- To develop and evaluate a novel pulmonary messenger RNA-lipid nanoparticle (mRNA-LNP) vaccine for bacterial lung infections.
- To assess the vaccine's ability to provide both rapid, innate immunity and sustained, adaptive immunity.
- To investigate the underlying immune mechanisms of this dual-phase protection.
Main Methods:
- Intratracheal delivery of a specifically engineered mRNA-LNP vaccine in female mice.
- Analysis of lung immune cell activation (neutrophils, macrophages) using transcriptomics and immune profiling.
- Assessment of bacterial clearance and protection against Pseudomonas aeruginosa strains.
- Evaluation of both early (antigen-independent) and later (antigen-specific) immune responses.
Main Results:
- The mRNA-LNP vaccine rapidly primes lung innate immune cells, enhancing phagocytic activity for early bacterial clearance.
- Vaccination induces robust antigen-specific adaptive immune responses, conferring sustained protection.
- A coordinated activation of innate and adaptive immune programs was observed.
- Effective protection was demonstrated against both laboratory and drug-resistant Pseudomonas aeruginosa strains.
Conclusions:
- Pulmonary mRNA-LNP vaccination elicits a dual-phase immune response, providing immediate and long-term protection.
- This vaccine design effectively bridges the post-vaccination immunity gap.
- The findings support pulmonary mRNA-LNP vaccination as a promising strategy against respiratory bacterial infections.
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