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A 3D Human Lung Tissue Model for Functional Studies on Mycobacterium tuberculosis Infection
Published on: October 5, 2015
Exaggerated Lung Inflammation Induced by Lung-Targeted mRNA-LNP Dampens Vaccines against Tuberculosis
Liyan Li1, Zeyu Yang1, Hong Liu2,3
1School of Materials Science and Engineering, Key Laboratory for Polymeric Composite and Functional Materials of Ministry of Education, Sun Yat-sen University, Guangzhou 510275, China.
Abstract:
The challenges in developing a tuberculosis (TB) vaccine stem from the complex life cycle of Mycobacterium tuberculosis (Mtb) and various bacterial proteins encoded by approximately 4000 genes. mRNA is easy to design and can accommodate multiple antigens, suggesting that it may be an effective TB vaccine technology. Here, we designed an mRNA encoding Ag85B and ESAT6 that was delivered by lung targeted lipid nanoparticles (LNPlung-mRNAA-E), intending to stimulate lung immunity to combat TB. To enhance the vaccine efficacy, we further cofabricated monophosphoryl lipid A (MPLA) with mRNA to evaluate the adjuvanted mRNA vaccine (LNPlung-mRNAA-E-MPLA). Both vaccines elicited robust CD4+ T cell response, resulting in markedly locally higher production of IFN-γ, TNF-α, and IL-2. As anticipated, the addition of MPLA further enhanced the immunogenicity of LNPlung-mRNAA-E. However, the Mtb challenge experiment showed that LNPlung-mRNAA-E-MPLA neither provided effective protection nor enhanced the immune protection primed by BCG (Bacillus Calmette-Guérin). The subsequent HE staining of the lung revealed that the LNPlung-mRNAA-E-MPLA induced pulmonary inflammation, leading to tissue damage. Moreover, the inflammatory cytokines including IL-6, IL-1β, and MCP-1 were significantly increased and the MPLA additive exacerbated the inflammatory process. Therefore, the lung targeted mRNA vaccine and MPLA adjuvant synergistically induced lung inflammation and weakened protection from Mtb infection. Thus, this work provides valuable implications for developing targeted lung vaccines: Addressing chronic lung inflammation induced by vaccine systems is critical for lung-targeted mRNA vaccines.
Insights
Lung-targeted mRNA vaccines encoding Ag85B and ESAT6, with or without monophosphoryl lipid A (MPLA), induced T cell responses but caused pulmonary inflammation. The adjuvanted vaccine exacerbated inflammation and weakened protection against tuberculosis (TB).
Area of Science:
- Vaccinology
- Immunology
- Infectious Diseases
Background:
- Developing an effective tuberculosis (TB) vaccine is challenging due to the complex nature of Mycobacterium tuberculosis (Mtb).
- Messenger RNA (mRNA) vaccines offer a flexible platform for delivering multiple antigens, showing promise for TB vaccine development.
Purpose of the Study:
- To design and evaluate a lung-targeted mRNA vaccine (LNPlung-mRNAA-E) encoding Ag85B and ESAT6 for TB.
- To assess the impact of monophosphoryl lipid A (MPLA) as an adjuvant on the efficacy and safety of the mRNA vaccine.
Main Methods:
- Constructed lipid nanoparticles (LNPs) targeting the lungs, encapsulating mRNA encoding Ag85B and ESAT6 (LNPlung-mRNAA-E).
- Co-formulated MPLA with the LNP-mRNA vaccine (LNPlung-mRNAA-E-MPLA) to create an adjuvanted formulation.
- Assessed immune responses (CD4+ T cells, IFN-γ, TNF-α, IL-2) and protection against Mtb challenge in a mouse model, alongside histological analysis of lung tissue.
Main Results:
- Both LNPlung-mRNAA-E and LNPlung-mRNAA-E-MPLA induced robust CD4+ T cell responses with increased local production of IFN-γ, TNF-α, and IL-2.
- The addition of MPLA enhanced immunogenicity but did not improve protection against Mtb challenge; neither vaccine formulation enhanced BCG-primed immunity.
- LNPlung-mRNAA-E-MPLA induced significant pulmonary inflammation, tissue damage, and elevated levels of IL-6, IL-1β, and MCP-1, with MPLA exacerbating these effects.
Conclusions:
- Lung-targeted mRNA vaccines, particularly when adjuvanted with MPLA, can induce detrimental pulmonary inflammation and impair protective immunity against TB.
- Strategies to mitigate chronic lung inflammation are crucial for the successful development of lung-targeted mRNA vaccines for infectious diseases.
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