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Title: The effect of viral vaccines on natural killer cell effector function
Author: Wagstaffe, H. R.
ISNI:       0000 0004 7964 7391
Awarding Body: London School of Hygiene & Tropical Medicine
Current Institution: London School of Hygiene and Tropical Medicine (University of London)
Date of Award: 2019
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Natural killer cells are large, granular, innate lymphoid cells that lie at the interface between innate and adaptive immunity and facilitate bidirectional crosstalk between the two systems. This has led to an abundance of research into vaccination induced priming of 'adaptive' or memory-like NK cell responses. Using human peripheral blood mononuclear cells for cross-sectional and vaccination studies in two distinct virus models, cytokine-dependent NK cell activation, and the effect of vaccination on these responses was investigated. Very low concentrations of IL-15 enhanced NK cell activation in response to inactivated influenza virus stimulation in vitro via augmented innate cytokine secretion from accessory cells, in particular IL-12 from myeloid dendritic cells. Similarly, after seasonal influenza vaccination, both accessory cell cytokine secretion and NK cell activation were enhanced compared to before vaccination in response to low dose IL-15 stimulation in vitro. This suggested that together with a vaccination-induced enhanced responsiveness to innate cytokines at the NK cell level (the generation of cytokine-induced memory like NK cells), an increased production of innate cytokines at the accessory cell level contributed to the overall enhancement in NK cell response post-vaccination. The effect of vaccination on NK cell effector function was further investigated in PBMC from heathy volunteers vaccinated with an Ebola glycoprotein expressing, vectored, prime-boost regimen vaccine (Ad26.ZEBOV/MVA-BN-Filo). Both inactivated influenza vaccination and Ebola vaccination increased the frequency and proliferation of less differentiated, CD56bright NK cells. Data described in this thesis also demonstrate for the first time that NK cells were activated indirectly by Ebola glycoprotein induced IL-12 and IL-18, independently of Ebola vaccination, and in contrast to influenza vaccination, there was no evidence of vaccine induced boosting of these responses. NK cell responses to Ebola GP were dependent on accessory cell TLR-4 engagement but were tightly regulated by CD14+ monocyte-derived IL-10. In addition to soluble antigen driven cytokinedependent activation, 21-day post-boost vaccination serum induced robust antibody-dependent NK cell activation of more differentiated subsets that varied with vaccine arm and correlated with antibody titre. Together, these studies demonstrate that two different types of vaccines against distinct viruses have similar impacts on the activation of less differentiated NK cells. Priming of both NK cells and myeloid cells for enhanced cytokinedependent NK cell responses after vaccination was not replicated across different vaccination models and may be a function dependent on the unique cytokine signatures induced by the respective antigens. These studies further our understanding of NK cells in post-vaccination effector responses, and may represent an avenue for improving future design of vaccines and adjuvants.
Supervisor: Goodier, M. R. ; Riley, E. Sponsor: Medical Research Council ; Innovative Medicines Initiative 2 Joint Undertaking
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral