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Title: Inducing IL-1β to increase vaccine efficacy
Author: Russell, Ryan
ISNI:       0000 0004 6496 0641
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2016
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Despite decades of research, there is no vaccine for respiratory syncytial virus (RSV). Many different approaches have been tested, but recently, small hydrophobic gene (SH) deletion mutants have been suggested as potential vaccine candidates since such strains are attenuated in vivo. The function of the SH protein is unknown, but multiple studies suggest that SH forms a viroporin capable of acting as an ion channel. Ion flux can activate inflammasomes, complexes based on Nod-like receptors (NLR), intracellular danger sensing receptors that catalyse the cleavage of highly inflammatory cytokines including IL-1β. Since it can form an ion channel, it was hypothesised that SH plays a role in inflammasome activation. The data presented here suggest that SH prevents activation of inflammasomes, reducing production of the key cytokine IL-1β, and it is shown that IL-1β is important for the control of RSV growth in vivo. Based on this finding, it was tested whether inflammasomes would make good targets for improving vaccination, through the use of specific adjuvants. The NLRs/inflammasomes have not been fully explored as adjuvant targets. Traditional adjuvants target pathways which are less functional in vulnerable populations, including neonates, making them less efficacious in such patients. Putative inflammasome activating compounds were tested in vitro for IL-1β inducing capabilities. Those found to induce such responses were taken forward into influenza vaccine and challenge models. It was found that one adjuvant, NanoSiO2, showed particularly strong potential as a vaccine adjuvant. Moreover, this compound appears to afford protection to severe flu infection in neonates, a group traditionally challenging to immunise. The NLRs and inflammasomes may therefore represent a viable target for activation during immunisation of neonates and other vulnerable groups. This study provides evidence for the rationale of NLR/inflammasome targeting during vaccination and demonstrates two new approaches to improve vaccines for difficult pathogens and at-risk populations.
Supervisor: Tregoning, John Sponsor: European Union
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral