Paediatrics (RCH) - Theses

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    Investigating the influence of BCG and hepatitis B vaccine on neonatal immune responses
    Cox, Lianne ( 2020)
    Neonatal infectious diseases result in an estimated 40% of neonatal deaths worldwide and contribute significantly to chronic morbidity. Childhood disease-specific immunisation is irrefutably linked to the decline in deaths from targeted infections over the last century. However, neonatal immunisation strategies are limited, in part, due to impairments in their adaptive immune function. Vaccine-induced protection from severe forms of tuberculosis (TB) with the Bacille Calmette-Guerin vaccine (BCG) and perinatally-acquired hepatitis B infection with the hepatitis B vaccine (HBV) are two exceptions, with these vaccines commonly administered to neonates worldwide. Evidence for heterologous (‘non-specific’) effects (NSEs) of various vaccines used in childhood, most notably for BCG, is increasing. This refers to the immunomodulatory capabilities of vaccines to influence immune outcomes beyond inducing protective immunity against the vaccine’s specific targeted disease. There is limited evidence for these effects in neonates, particularly for HBV. The research reported in this thesis aimed to explore the influence of BCG, HBV and concurrent administration of both vaccines at birth on the neonatal immune responses to unrelated antigens compared with unvaccinated babies in a randomised control trial (RCT): The Early Life Vaccine and Immunity Study (ELVIS). Neonatal blood samples from 128 participants, collected seven days after randomisation, were stimulated with various unrelated antigens for 20 hours. Cytokine responses, measured in the supernatants by an enzyme-linked immunosorbent assay (ELISA) method, were analysed using non-parametric statistical tests to determine differences in median responses between the four groups: BCG alone, HBV alone, concurrent BCG and HBV and the unvaccinated control group. I found minimal differences in the median in vitro cytokine responses to all stimulants between the four groups. However, both vaccines independently influenced cytokine-stimulant responses. Effects on responses were strongest for BCG-vaccinated babies, but only decreased interferon gamma (IFN-gamma) responses to the Toll-like receptor (TLR) ligand resiquimod (R848) and monocyte chemoattractant protein-1 (MCP-1) responses to heat-inactivated E. coli were significantly different from controls. Combined vaccines tended to induce similar cytokine-stimulant response patterns as BCG alone, although for some cytokine-stimulant pairs, the BCG-induced effects were mitigated by HBV and vice versa. This study adds to the evidence for NSEs of vaccines in neonates. It is the first study to investigate the influence of HBV immunisation on immune responses to unrelated antigens, finding no statistically significant differences in median cytokine responses compared with controls. The finding that concurrent vaccination with HBV and BCG at birth induced the same cytokine-stimulant response pattern as BCG alone, suggested that cytokine responses to unrelated stimulants are driven by BCG. This is also the first study to show that in neonates concurrent HBV and BCG vaccination at birth weakens the NSEs of BCG for certain cytokine-stimulant pairs. Further research into neonatal vaccine NSEs are warranted. Future studies should explore and further investigate the clinical relevance of certain cytokine-stimulant response signatures identified in my thesis and the mechanism for these observations in neonates. These results will direct research on how we could potentially exploit any beneficial vaccine NSEs to provide protection against infection in the very young.
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    Vascular phenotypes and innate immune responses following Kawasaki disease and toxic shock syndrome
    Chen, Katherine Ya-Hui ( 2017)
    Background: The pathogenesis of cardiovascular disease begins in early life. Inflammation is increasingly recognised to play a pivotal role in the initiation and progression of atherosclerotic cardiovascular disease. It is unclear whether acute childhood vascular inflammation results in heightened cardiovascular risk and reflects an underlying increased inflammatory predisposition. Understanding the host immune susceptibility determinants and the impact of early life vascular inflammation on the subsequent development of subclinical atherosclerosis could assist in improving diagnostics, prognostication, and treatment. This thesis focuses on two childhood diseases characterised by acute inflammation involving the cardiovascular system, Kawasaki disease (KD) and toxic shock syndrome (TSS). Aims: Part 1: To identify the macro-and microvascular phenotypes associated with subclinical atherosclerosis in individuals following KD or TSS. Part 2: To investigate differences in innate immune responses following KD or TSS that might underlie host susceptibility. Methods: Part 1: A case-control study of 60 KD, 22 TSS, and 60 control participants; cases were investigated at least two years after their acute illness. Non-invasive measurements of extra-cardiac arterial structure (carotid and aortic intima-media thickness) and function (pulse wave velocity, carotid artery distensibility and diameter compliance) were done. Retinal microvascular parameters were measured in both an Australian and Singaporean cohort. Part 2: In-vitro cytokine production induced by Toll-like receptor and inflammasome ligand stimulation was measured in whole blood. Results: Part 1: Compared to control participants, Individuals following KD had increased aortic intima-media thickness and reduced carotid distensibility, indicative of heightened cardiovascular risk. Furthermore, KD participants, particularly of Asian ethnicity, had wider retinal venules with an incremental increase in those with coronary artery abnormalities, also in keeping with an increase in cardiovascular risk. Individuals following TSS had reduced retinal fractal dimension but no other adverse differences in the macro- and microvascular parameters. Part 2: Compared to control participants, individuals following KD had reduced interleukin (IL)-1 receptor antagonist production in response to stimulation with double stranded RNA and increased IL-6 production in response to incubation with Lyovec™ (a lyophilised cationic lipid-based transfection reagent). Toxic shock syndrome participants had increased pro-inflammatory cytokine production (interferon-, IL-1, IL-6) in response to stimulation with bacterial ligands (peptidoglycan, lipopolysaccharide). Conclusions: Part 1: Extra-cardiac vascular phenotypes indicative of increased cardiovascular risk have been found in individuals following KD. These findings suggest that these individuals should minimise their modifiable cardiovascular risk factors. Limited evidence for increased cardiovascular risk was found following TSS, suggesting that differing causes of childhood vascular inflammation may have varying impact on the development of subclinical atherosclerosis. Part 2: Individuals with previous KD or TSS have decreased anti-inflammatory and increased pro-inflammatory responses (respectively) to innate immune stimulation. The findings indicate either an inherent immunological susceptibility and/or trained innate immunity following the acute illness.