Sunday, May 18, 2025
5/18/2025
Molecular basis of BCG vaccine sub-strain heterogeneity - PROJECT SUMMARY Vaccination against tuberculosis (TB) uses live bacillus Calmette-Guérin (BCG) given at birth. Unfortunately, variable efficacy is observed of between 0-80%, but the reasons are complex, involving host, vaccine and environment. Danish/Japan/Russia/Moreau BCG are the most widely used and produced at different facilities. Differences in protection are controversial, but epigenetic trained immunity (TRI) and immunogenicity differences can be demonstrated in laboratory models. If we are to improve BCG or design a replacement, it is critical that the differences are better understood in humans. Since new vaccines must first prove their value in animal models, it is important to correlate differences observed with TRI and protection in humans. In our preliminary studies, we found that Danish (BCGD) and Japan (BCGJ) strains differ in protective efficacy and there are differences in the host response in both mice and guinea pigs (GP). We take advantage of this unique dataset in animals, combined with differences we observed with TRI in human macrophages and our recent blinded, randomized, placebo controlled Tice BCG vaccination study in humans to better understand BCG induced protection. Since the BCG substrains are very closely related and extremely well characterized, they offer a rare opportunity to enhance the protective efficacy of TB vaccines. We found that a series of differences between the BCG substrains impacting TRI and the host response that can be used to analyze the roles of TRI and adaptive immunity in vaccine efficacy. In this application we will dissect TRI and the host response to BCG substrains in animal models and correlate the specific mechanisms involved with that in humanized mice and humans. This will be accomplished by two aims: 1) Compare animal model protective biosignatures to PBMCs from BCG vaccinated humans. Our working hypothesis is that the BCG substrains that differ in efficacy in animal models will differ in induction of TLR2, TGFβ, NFκβ, Hsp90 and CCL5, which will correlate with TRI and BCG vaccination in humans. Our preliminary data identified differences in protection and the host response for BCGD and BCGJ. In this aim we will use scRNA-seq, scATAC-seq and immune profiling to analyze the TRI and protective response to BCGD, BCGJ, Pasteur (BCGP) and Tice (BCGT). These data will be correlated with the BCG substrains and responses in our unique BCGT/placebo treated cohort of 636 human subjects. 2) Determine the mechanisms for induction of TRI by BCG substrains in human APCs and its relationship to adaptive immunity in humanized mice. Our working hypothesis is that BCG induces TRI by activating dectin1 and Mincle (aka. C-type lectin like receptors; CLRs) in human macrophages (MDMs). Our preliminary data found that BCG substrains epigenetically alter MDMs, impacting antigen presentation, autophagy and antigen processing. We will determine the epigenetic basis of antigen processing and presentation in MDMs and humanized mice, examining efficacy by aerosol challenge with TB.
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