Characterising the cytokines associated with trained innate immunity in BCG vaccinated non-human primates
Characterising the cytokines associated with trained innate immunity in BCG vaccinated non-human primates
Led by Dr Laura Sibley (UKHSA, UK)
Project Aims
The Bacille Calmette-Guerin (BCG) vaccine has been in use as the primary vaccine against tuberculosis (TB) for 100 years and is given widely at birth in countries where TB is endemic. BCG has been demonstrated to reduce infant mortality by up to 40% against unrelated childhood diseases. The mechanisms behind this are not well understood, but the hypothesis is that BCG causes epigenetic reprogramming in monocytes and NK cells, giving them memory-like characteristics that mean they can recognise and remove unrelated pathogens - a mechanism termed 'trained innate immunity'. Current research has identified cytokines produced when cells are stimulated with unrelated microorganisms including IFNγ, IL-1β and TNFα in humans and mice, and BCG vaccination is able to protect against experimental infection with Yellow Fever and Candida albicans respectively. In this pilot project, the aim is to investigate the cytokines associated with trained innate immunity induced after BCG vaccination in the non-human primate model where BCG is delivered in different ways; including BCG delivered by different routes (intradermally, intravenously, by aerosol); BCG given close to birth, to different macaque species where the efficacy conferred by BCG differs and to determine responses duration and the impacts on TB infection. At UKHSA Porton Down we have a huge archive of samples from numerous non-human primate vaccine evaluation studies which will be used to address these questions, and will enable the relationship between the responses to be revealed and the outcome following infection with Mycobacterium tuberculosis (M.tb) to be explored. The findings from this work will aid in the design of future vaccines to ensure that any novel TB vaccine to replace BCG can also induce trained immunity, so that children are not left vulnerable to these other infections if they are no longer given BCG. Analysis of the repsonses that comprise the trained immune responses after different routes and timings of BCG vaccination, will inform on how BCG is used in the future and may improve the usefulness and efficacy of BCG against TB.
Project Outcomes
Trained innate immunity is a phenomenon that has been observed in people and tested in animal models whereby BCG vaccination (the current vaccine for tuberculosis (TB)) confers protection against infection by pathogens that are unrelated to TB. In this project, I have been able to optimise a trained immunity assay using rhesus macaque PBMCs and applied it to different sets of samples from vaccinated macaques to look at whether different routes of BCG vaccination, or age vaccination was given affect trained innate immune responses. The response to stimulation with E. coli, S. aureus and C. albicans after intradermal BCG was characterised over a 16-week period and showed that a variety of different cytokines were produced, which varied depending on which stimulation was used. I also studied samples from macaques vaccinated with BCG intravenously, as this route of vaccination has been shown to be more protective against M.tb in macaques, and against unrelated pathogens in mice, and found that cytokines produced were generally more mycobacteria-specific rather than the towards the other microorganisms at the time point we measured. When comparing unvaccinated macaques against those vaccinated with BCG at birth, we found there were some differences, but most responses were higher in the unvaccinated group, which could suggest that there is a more controlled response in infant vaccinated macaques. Samples from macaques from different breeding colonies suggested that there could be an impact of environment and diet on innate responses to microorganisms. Research has suggested that the innate immune status influences adaptive immune responses, so by looking at baseline responses we saw that some cytokines at baseline correlated with BCG-specific IFNγ ELISPOT responses after vaccination, as well as cytokine production in the trained innate immune assay. Correlation analysis highlighted that some trained innate immune signatures did correlate with a better outcome after infection. Overall, we now have a better understanding of what the trained immunity cytokines look like following BCG vaccination, and we wish to continue the work further to look at epigenetic and metabolic reprogramming of monocytes and use flow cytometry to look at the cell populations involved in more detail.
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