| Popis: |
The vaccine field generally accepts that the induction of high-titre antibodies will be necessary to prevent the invasion of erythrocytes utilising vaccines targeting the blood-stage of malaria. Protein-in-adjuvant formulations are commonly used to achieve such responses. However, their clinical development can be limited by the reactogenicity of some of the most potent pre-clinical adjuvants and the cost and complexity of licensing new adjuvants for human use. Work in this thesis describes the comparative assessment of classical adjuvants such as alum to new pre-clinical adjuvants and adjuvants in clinical development for the induction of high and sustained antibody and T cells responses. These adjuvants induced a broad range of antibody responses when used in a three-shot protein-in-adjuvant regime using the model antigen ovalbumin and leading blood-stage malaria vaccine candidate antigens. Surprisingly, this range of antibody immunogenicity was greatly reduced and antibody responses were of a comparably high magnitude when a protein-in-adjuvant vaccine was used to boost antibody responses primed by an AdHu5 vaccine recombinant for the same antigen. This adenovirus prime, protein boost regime also induced a more cytophilic antibody response and demonstrated improved efficacy of merozoite surface protein-1 protein vaccines against a high-dose Plasmodium yoelii blood-stage challenge. Investigating the underlying differences between the vaccine platforms used suggests the improved boosting observed following an adenovirus prime is not due to differences in antigenic dose exposed to the immune system or extended immunisation intervals between adenovirus and protein vaccines, but rather appears to be inherent to the adenoviral vector, which induces more germinal centre cells and T follicular helper cells. Attempts to further enhance the immunogenicity of viral vectors through the direct addition of the adjuvants chloroquine and Adju-Phos® was not successful. |
