For both influenza viruses and hepatitis C viruses, T cell responses to conserved antigens are one strategy for the human host to control the spread of infection. Such T cell responses can be generated with the use of viral vectored vaccines. Initially I show that the viral vectored vaccine MVA-NP+M1 can boost memory T cell responses to influenza A virus in adults aged over 50 years old. However within this group, MVA-NP+M1 had reduced immunogenicity in adults who were aged over 70 years old. The influenza virus-specific T cell responses comprised both CD4 and CD8 T cells, and were capable of secreting multiple Th1 cytokines. I then show that MVA-NP+M1 can be safely co-administered alongside seasonal influenza vaccine. The combination does not interfere with the peak T cell response that normally occurs 1 week following MVA-NP+M1. There was a statistically significant increase in antibodies to the H3N2 strain when the vaccines were co-administered, suggesting that the MVA-NP+M1 can act as an adjuvant. The efficacy of MVA-NP+M1 in humans had been previously evaluated in an influenza virus challenge study. I used a whole blood transcriptome approach to improve the classification of outcomes following influenza virus challenge. For subjects with laboratory-confirmed influenza, individuals with moderate/severe symptoms were found to have a distinct transcriptional signature comprising over 2,000 genes. I used a machine learning algorithm to reduce this variation down to just six genes (CCL2, SEPT4, LAMP3, RTP4, MT1G and OAS3). I validated this finding using expression data from an independently conducted challenge experiment. Data from these six genes was successfully able to predict symptomatic and asymptomatic cases with 89% and 100% accuracy respectively. To induce T cell responses to hepatitis C virus, I used the vaccines ChAd3-NSmut and MVA-NSmut in a prime-boost regimen. While the combination was highly immunogenic in healthy young adults, MVA-NSmut alone was unable to prime immune responses. The magnitude of T cell responses to the vaccine immunogen was correlated with the breadth of the T cell responses to different epitopes. Re-administration of the same two vaccines after a short time interval (8 weeks) did not improve upon previous peaks in T cell response. However with a longer time interval (> 34 weeks), some individuals were able to achieve higher frequencies of virus-specific T cells compared to the first round of vaccines. A whole blood transcriptome approach was used to study gene expression in volunteers vaccinated with ChAd3-NSmut and MVA-NSmut. Vaccination with MVA-NSmut results in a very strong, but relatively short-lived host gene expression signature. In contrast, the transcriptional response seen following ChAd3-NSmut was much less pronounced. A comparison of the functional analysis of gene lists from both vaccines showed that similar pathways were being activated and repressed.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:640068 |
| Date | January 2014 |
| Creators | Antrobus, Richard |
| Contributors | Gilbert, Sarah |
| Publisher | University of Oxford |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://ora.ox.ac.uk/objects/uuid:a3efad5e-d619-4641-8c05-2d4e336a10dc |
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