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Title: Vaccine design for global health pathogens
Author: Padron-Regalado, Eriko
ISNI:       0000 0005 0291 2844
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2019
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MERS and malaria are two global infectious diseases with no commercial vaccines available. This thesis describes work undertaken to develop and improve adenovirus-based vaccines for these infectious diseases. In the case of MERS coronavirus, a highly effective heterologous prime-boost vaccination based on a chimpanzee adenovirus was created (ChAdOx1). In order to further optimise its immunogenicity, previously described genetic designs modulating transgene expression were evaluated. It was found that ChAdOX1 encoding the MERS S glycoprotein induced high levels of antigen-specific immune responses. Such levels were further increased by boosting with an MVA encoding the same antigen. The inclusion of a tissue-plasminogen activator leader sequence (tPA-LS) had a positive impact on the levels of antigen-specific antibody responses, while the inclusion of the early promoter F11 in the MVA had a positive impact on the levels of antigen-specific cellular responses. In the case of malaria, the immunological effects of recently discovered adjuvants were explored. Spermidine induced higher levels of antigen-specific CD8+ T cell responses from spleens, induced by an adenovirus vaccine model 3 (AdHu5). Nevertheless, no influence of the spermidine was found on PBMCs. In the case of 2'3'-cGAMP, the adjuvant enhanced the immunogenicity of the capsid proteins of the adenovirus, but not the transgene antigens. An optimisation of the use of this adjuvant using bivalent adenoviruses resulted in a significant enhancement in transgene immunogenicity. Furthermore, it was found that IFN-β, induced during the activation of the cGAS/STING pathway, affected adenovirus transgene expression and immunogenicity. It is hoped that the results presented in this thesis contribute to the advancement in the creation of safe and effective vaccines for MERS coronavirus and malaria.
Supervisor: Hill, Adrian ; Spencer, Alexandra ; Douglas, Alexander Sponsor: CONACYT Mexico ; Jenner Institute (University of Oxford)
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available