An RNA-Based Vaccine Platform for Use against Mycobacterium tuberculosis

Area of Science:

• Immunology
• Vaccinology
• Microbiology

Background:

• Tuberculosis (TB) remains a significant global health burden, complicated by the pathogen's complexity and varied disease stages.
• Identifying immune correlates of protection for TB vaccines has been challenging, hindering vaccine development.
• Current vaccine strategies require novel platforms to overcome these hurdles.

Purpose of the Study:

• To evaluate two novel prophylactic vaccine platforms for Mycobacterium tuberculosis (M.tb).
• To assess the immunogenicity and efficacy of a fusion protein and a replicating-RNA (repRNA) vaccine candidate (ID91).
• To investigate the impact of single and prime-boost immunization strategies against M.tb challenge.

Main Methods:

• Utilized C57BL/6 mice for prophylactic vaccination studies against low-dose and ultra-low-dose M.tb H37Rv aerosol challenge.
• Developed ID91 as a fusion protein with a synthetic TLR4 agonist and as a repRNA formulated in a nanostructured lipid carrier.
• Administered single prophylactic immunizations and heterologous prime-boost strategies (RNA-prime, protein-boost, combination).

Main Results:

• Both protein subunit and repRNA vaccine platforms demonstrated a reduction in pulmonary bacterial burden after single immunization.
• Prime-boost strategies, particularly heterologous RNA-prime/protein-boost and combination immunizations, achieved the greatest reduction in bacterial burden.
• Unique humoral and cellular immune response profiles were observed in the most effective prime-boost groups.

Conclusions:

• Replicating-RNA (repRNA) platforms represent a viable and promising system for developing TB vaccines.
• Further investigation of repRNA vaccines incorporating high-priority M.tb antigens with CD4+ and CD8+ T-cell epitopes is warranted.
• Heterologous prime-boost immunization strategies offer enhanced efficacy against M.tb infection.