Paediatrics (RCH) - Theses
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ItemSafety of Bacille Calmette-Guérin vaccination and revaccination( 2022-12)Bacille Calmette-Guerin (BCG) vaccine, derived from live-attenuated Mycobacterium bovis, is commonly given as a single dose in infancy to protect against tuberculosis (TB) in high TB-prevalence settings. There is growing interest in BCG revaccination for the protection of adolescents and adults against TB. Increasing recognition of potential novel applications for BCG to protect against diseases other than TB also mean that BCG vaccination (and revaccination) may become increasingly used in broader age groups and settings. For these reasons, a more comprehensive and detailed understanding of the safety of BCG vaccination and revaccination, particularly in adults, is necessary to help inform public health policy. My PhD research aimed to evaluate the incidence and predictors of reactions (normal, accelerated and adverse) to BCG vaccination, the impact of revaccination on BCG reactions, and the clinical management of adverse reactions to the vaccine. These aims were investigated using active safety surveillance of BCG vaccination reactions within an international randomised controlled trial of nearly 7000 adult participants – the BRACE Trial (BCG vaccination to reduce the impact of COVID-19 in healthcare workers), as well as through two systematic reviews and a meta-analysis of BCG vaccination safety in children. My thesis comprises three sections characterising reactions following BCG vaccination and revaccination: (i) the normal reaction; (ii) accelerated reactions; and (iii) adverse events. The first section reports a cohort study to assess the prevalence, factors influencing formation and vaccinee perception of BCG scarring (normal BCG reaction) following vaccination and revaccination in adults. The second section includes a systematic review and meta-analysis to investigate the clinical significance of an accelerated BCG reaction in children, reporting an association with prior mycobacterial exposure. A cohort study is then presented that evaluated the incidence and clinical implications of an accelerated BCG reaction in asymptomatic adults in low and high TB-prevalence settings. The third section includes a systematic review of the management strategies for BCG-associated lymphadenitis and injection site abscess in children. This is followed by a cohort study to assess the incidence and risk factors (host immune- and vaccination-related) for BCG-associated lymphadenitis and injection site abscess in adults. An additional cohort study in adults assesses the safety of co-administration of BCG with the influenza vaccine. The overall incidence of local adverse events and serious adverse events in the BRACE trial is then described, as well as the impact of previous BCG vaccination on local injection site reactions. Overall, BCG revaccination in adults was associated with increased frequency of normal (scar), accelerated and local adverse reactions (injection site abscess and lymphadenitis), compared to receiving BCG for the first time. Younger age was also associated with increased frequency of normal and local adverse reactions. Similarly, female sex was associated with an increased frequency of normal reactions and lymphadenitis following BCG vaccination, as well as increased frequency of accelerated BCG reactions. Latent TB infection was found to predispose to an accelerated BCG reaction, but was not associated with injection site abscess. Nonetheless, regardless of prior BCG vaccination status, age or sex, the majority of reactions were mild in nature, localised to the injection site and resolved without intervention. In summary, the studies in my thesis indicate that BCG vaccination and revaccination have an acceptable safety profile in children and adults.
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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.