Paediatrics (RCH) - Theses
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ItemThe innate immune mechanisms underlying the off-target effects of Bacillus Calmette-Guérin vaccine in infants( 2022-12)Bacillus Calmette Guerin vaccine (BCG) is administered to over 100 million newborn infants globally each year with the aim of protecting against tuberculosis. In addition to its specific anti tuberculous effects, BCG vaccine has off target effects that protect against a broad range of non mycobacterial infections in both children and adults. Immunological studies have implicated trained immunity in the mechanism underlying the off target effects of BCG vaccine in adults. Trained immunity is a de facto innate immune memory underpinned by the functional epigenetic and metabolic reprogramming of innate immune cells, such as monocytes. While much research has focused on elucidating the immunological mechanisms underlying the off target effects of BCG in adults, few studies to date have investigated the immunological mechanisms in children. Using samples from a well characterised sub cohort of 130 infants from MIS BAIR, a randomised trial of neonatal BCG vaccination in Australia, the projects in this thesis aim to characterise the phenotypic, functional, and epigenetic effects of neonatal BCG vaccination on the infant immune system in the first year of life. Chapter 2 of this thesis sought to better understand the role of vaccination and natural infection in shaping the human epigenome by a systematic review of the literature. This review identified a paucity of paediatric studies and highlighted a need for further research investigating the epigenetic mechanisms underlying the off target effects of BCG vaccine in children. This knowledge gap is addressed by the subsequent projects of this thesis. Immunological studies in infants are hampered by the ethical and logistical challenges of obtaining blood samples from this age group. Optimisation experiments detailed in Chapter 3 led to the refinement of laboratory methods that generate high dimensional immunological data from small volume infant blood samples containing as few as 3 million peripheral blood mononuclear cells (PBMC). Multi parameter flow cytometry was used to comprehensively profile and sort cell populations of interest for downstream analysis. The monocyte fraction was then used for parallel DNA methylation analysis and ex vivo heterologous stimulation assays. This analysis pipeline produced rich normative data on baseline immune cell profiles and monocyte cytokine responses in BCG naive infants. Subsequent studies in Chapters 4 and 5 found that BCG vaccinated infants have increased proportions of circulating classical and non classical monocytes, and activated regulatory CD4 T cells, compared to BCG naive infants at 13 months of age. Monocytes from BCG vaccinated infants also have an attenuated inflammatory response following heterologous stimulation and retain a DNA methylation signature of early life BCG exposure. Genes associated with this signature are involved in interferon signalling pathways and viral immunity. In summary, the studies in this thesis demonstrate that neonatal BCG vaccination induces durable changes in circulating immune cell profiles, monocyte cytokine responses and DNA methylation remodelling that persist over the first year of life. These changes are different to those observed in adults and strengthen evidence that immune responses to BCG vaccination are age dependent. Collectively, these findings contribute to a better understanding of the immunological mechanisms underlying the off target effects of BCG vaccine in infants that will inform the development of new immunomodulatory therapies and guide global vaccine policy.