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Title: Of mice and MenB : assessing the immune mechanisms underlying meningococcal capsular group B vaccines in mice
Author: Sheerin, Dylan
ISNI:       0000 0004 8503 273X
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2019
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Neisseria meningitidis is the causative agent of invasive meningococcal disease (IMD) which claims between 50,000 and 135,000 lives worldwide annually. Disease caused by the capsular group B meningococcus (MenB) is the leading cause of infectious death in UK infants. A four component vaccine, 4CMenB, has been developed to prevent IMD caused by this capsular group, but is associated with a high incidence of fever in infants and requires multiple doses to induce adequate protection. A novel adenovirus-based vaccine encoding the MenB factor H binding protein (fHbp) with an N-terminal signal sequence (Ad-fHbp) has been developed at the Oxford Vaccine Group and was found to induce high titres of protective antibody after a single dose in mice. The central aims of the work presented in this thesis were to elucidate the immune mechanisms underlying the reactogenicity of 4CMenB and the immunogenicity of Ad-fHbp. 'Systems vaccinology' has provided many insights into vaccine-induced responses by combining high-throughput sequencing with conventional immunogenicity assays to characterise the gene signatures and immunological pathways underlying them. However, the RNA- sequencing (RNA-seq) component of such studies can be compromised by the impact of computational choices on the final differential gene expression (DGE) call. A novel DGE pipeline was developed in the present study to mitigate the impact of this computational 'noise'. A 'systems' approach was then taken to comparatively assess 4CMenB vaccine combinations and components in order to determine the cause of fever in a mouse immunisation model. Using a combination of RNA-seq, temperature, and inflammation markers, the reactogenicity was ultimately attributed to the membrane-bound endotoxin contained in the outer membrane vesicle component of the vaccine. To explore the phenomenon of the early, sustained protective immune response induced by Ad-fHbp, a panel of N-terminal signal sequence insertion/deletion variants of the antigen were comparatively assessed for in vitro expression from mammalian cells and for immunogenicity in mice. The full-length sequence demonstrated superior early expression and induction of bactericidal antibody and was also found to significantly boost antigen-specific T cell responses when incorporated ahead of other adenovirus-encoded bacterial antigens, highlighting it's potential as an immune-enhancing sequence element for other viral vectored vaccine transgenes. Finally, antigen-specific immunological pathways were defined for the fHbp transgene product by comparative transcriptomics. The work presented in this thesis contributes to our understanding of what constitutes a well-tolerated and immunogenic meningococcal vaccine.
Supervisor: Dold, Christina Sponsor: Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Genetics ; Microbiology ; Transcriptomics ; Vaccinology ; Systems biology ; Immunology