UC Berkeley

Before the emergence of SARS-CoV-2 and the ensuing COVID-19 pandemic, the pathogenic bacteria Mycobacterium tuberculosis was the world’s leading infectious disease killer. In 2020, an estimated 1.6 – 1.8 million people worldwide died of tuberculosis (TB) disease, comparable to the ~1.9 million lives claimed by COVID-19. However, while highly effective vaccines were rapidly developed for COVID-19, the sole approved TB vaccine, Bacillus Calmette-Guérin (BCG), is only moderately effective at blocking infection and has not prevented the TB pandemic despite 100 years of use and more widespread distribution that any vaccine in history. This highlights the urgent need for improved vaccines to prevent TB, which begins with a more complete understanding of the protective immune response to TB and the development of new strategies to effectively induce this immune response in patients. Here, we demonstrate a novel TB vaccine strategy using small molecule cyclic di-nucleotide (CDN) adjuvants to activate the STING pathway of the innate immune system. Subcutaneous administration with a CDN adjuvanted protein subunit vaccine for TB leads to protection in mice that is equivalent to that afforded by BCG. This protective efficacy is STING-dependent but Type I IFN-independent and correlates with a significant population of Th17 cells that are not present in the lungs of unvaccinated mice. Similarly, intranasal immunization leads to a multifaceted pathogen-specific CD4 T cell response characterized by both Th1 and Th17 cells, as well as a non-classical Th1-Th17 population that co-expresses IFN-γ and IL-17. Intranasally vaccinated mice also benefit from enhanced CD4 T cell localization to the lung parenchyma and homing to granulomatous lung lesions compared to unvaccinated mice. This distinct CD4 T cell response leads to protection against infection that is significantly greater than BCG and is more effective than any protein subunit vaccine tested against M. tuberculosis in mice to date. Full protective efficacy after intranasal immunization is dependent on both IFN-γ and IL-17 and, in contrast to subcutaneous administration, relies on Type I IFN signaling. Importantly, intranasal immunization with a CDN vaccine is also capable of boosting BCG-mediated immunity. These results demonstrate that stimulation of the STING pathway is sufficient to induce a protective CD4 T cell response to an intracellular pathogen and contribute to our knowledge of CD4 T cell subsets that can mediate protection against M. tuberculosis infection.