Using Zeolitic Imidazolate Frameworks for Creating an Intranasal Depot Effect and Development of a Novel Tuberculosis Subunit Vaccine

Tuberculosis (TB) is the second leading cause of deaths from infectious diseases in the world after Covid-19. Despite the great strides taken in vaccine development over the last few decades, TB prevention still relies on the century-old BCG formulation, whose efficacy widely varies amongst different populations. Whole cell attenuated vaccines for such pathogenic diseases are a risky avenue of research. Decades of subculturing are required to attenuate the strains, and yet there is always a risk of reverting to virulence. We have hence developed a subunit vaccine candidate which combines two novel antigens, a powerful adjuvant, and a slow-release system using MOFs for depot effect. CtpV and MctB are two membrane-bound metal transporter proteins present on the surface of Mycobacterium tuberculosis that are potential virulence factors of TB and can be used to induce a T-cell mediated response upon vaccination. Class A CpG—a synthetic reproduction of bacterial DNA—has been widely investigated as an adjuvant in research models and fits into our formulation well as it also activates T-cells. It is worth noting that many similar subunit vaccines that fall short in clinical trials are unable to produce high enough antibody titers compared to whole cell vaccines. This is primarily attributed to short exposure time of delicate biomaterials like liposomes, that degrade in the body fast. Our goal is to combat this using zeolitic imidazolate frameworks (ZIF), a metal-organic framework that can be synthesized in biofriendly conditions to build a protective coating around the biomaterial. ZIF degrades slowly inside the body, and a vaccine coated with ZIF would slowly release antigens and provide prolonged presentation, giving the immune system time to develop more antigen-specific antibodies. This formulation also allows us to vary the ZIF coating thickness in order to optimize the duration of antigen presentation. We recently concluded an extensive study which demonstrates the biosafety of a wide range of ZIF doses when delivered intranasally in mice as a first step of this investigation. We found that there was no significant difference in the serum protein and enzyme levels and the lung diffusing capacity of mice administered even up to 1 mg ZIF per animal. No tissue damage was observed in the nasal turbinates, trachea, or lungs either. We are currently working on optimizing the various aspects of our vaccine for an ideal immune response and benchmarking our vaccine candidate’s performance against BCG.