Protective mRNA Vaccines Against Tuberculosis

Protective mRNA Vaccines Against Tuberculosis. Summary. Tuberculosis (TB), caused by Mycobacterium tuberculosis (M. tb), remains a significant global health challenge, affecting approximately one-third of the world’s population and resulting in nearly 1.4 million deaths annually. The existing vaccine, M. bovis BCG (BCG), offers variable protection, with efficacy ranging from 0% to 80%. Our previous research has identified several innovative platform technologies aimed at enhancing vaccine development for major infections impacting both human and animal health. Notably, we have developed unique nano-adjuvant systems (NAS) that have demonstrated effectiveness against respiratory infections, including coronavirus and M. avium. In this project, we will utilize our expertise in tuberculosis vaccine development and nanoparticle vaccine platforms to assess the protective efficacy of a novel combination vaccine against TB. Our approach incorporates cutting-edge mRNA vaccine technology delivered via QuilA-DOTAP (QTAP), a novel lipid nanoparticle delivery adjuvant that ensures stable mRNA transcript delivery at various temperatures suitable for use in TB- endemic regions. Preliminary analyses of QTAP-adjuvanted combination mRNA vaccine encoding three mycobacterial antigens (Ag85B, Hsp70, and EsxH), referred to as QRNA, have shown robust protective immunity in mouse models challenged with both low and high doses of the virulent M. tb Erdman strain. In this project, we plan to First; examine the safety and immunogenicity of QRNA vaccines in variable murine models using both immune-compromised (Rag1-/-) and immune-competent (C3HeB/FeJ) murine models. Second; analyze the protective role of QRNA vaccine as a homologous or heterologous vaccine primed with BCG against challenge with M. tb Erdman (lineage 4, laboratory strain) or HN878 (lineage 2, hypervirulent clinical strain). Finally, we will assess protective immunity of QRNA vaccines in guinea pigs to identify vaccine-induced immune correlates of protection elicited by the mRNA vaccine candidates in guinea pigs, a TB model that mimic human infection. Once achieved, results from those aims will enhance our understanding of RNA-based immunization against TB. Future projects will further dissect the generated immunity in non-human primates, a more relevant model for human TB. Project Number: 1R01AI196011-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: ADEL TALAAT | Institution: UNIVERSITY OF WISCONSIN-MADISON, MADISON, WI | Award Amount: $717,003 | Activity Code: R01 | Study Section: Vaccines Against Infectious Diseases Study Section[VID] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01AI19601101