Exaggerated Lung Inflammation Induced by Lung-Targeted mRNA-LNP Dampens Vaccines against Tuberculosis

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 (LNP_lung-mRNA_A-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 (LNP_lung-mRNA_A-E).
• Co-formulated MPLA with the LNP-mRNA vaccine (LNP_lung-mRNA_A-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 LNP_lung-mRNA_A-E and LNP_lung-mRNA_A-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.
• LNP_lung-mRNA_A-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.