Consistent efficacy in human clinical trials has been achieved by two leading malaria vaccine candidates encoding either the P. falciparum circumsporozoite (CSP) or thrombospondin-related adhesion (TRAP) proteins. However, protection in humans relies on high antibody (Ab) titers or potent T cells, respectively, when these antigens are used individually. Therefore, a concurrent induction of both anti-CSP antibodies and TRAP-specific T cells may further improve the protective efficacy associated with these immunogens. This thesis investigates the protective potential associated with CSP and TRAP combination vaccines by employing a pre-clinical Plasmodium berghei (P. berghei) mouse malaria challenge model. Depletion of CD4<sup>+</sup> and CD8<sup>+</sup> T cells indicated that protection by the CSP antigen relied solely on antibodies while TRAP protected through CD8<sup>+</sup> T cell responses. Moreover, the administration of relatively small amount of anti-CSP monoclonal antibodies (mAb) substantially enhanced the sub-optimal protection elicited by TRAP. A way to maximize both, anti-CSP antibodies by adenovirus/protein (Ad-P) prime-boost vaccinations and anti-TRAP T cell responses using adenovirus/modified vaccinia strain Ankara (Ad-M), was explored. Combination of the two approaches stimulated optimal humoral and cellular responses that afforded sterile protection in the C57BL/6 animal model. Additional analyses of the effector functions of Abs indicated that the efficacy of this vaccine relied on a two-stage attack against the parasite: anti-CS antibodies reduced the number of sporozoites reaching the liver, thus decreasing the number of infected hepatocytes required to be eliminated by the dual action of natural killer (NK) cells and CD8<sup>+</sup> T cells. These proof-of-concept studies using a wild-type (wt) P. berghei challenge model allowed progression towards the development of human malaria Plasmodium vivax (P. vivax) vaccines using PvCSP and PvTRAP antigens. The immunogenicity of PvCSP and PvTRAP-based vaccine candidates was assessed in multiple mouse strains. Additionally, transgenic (tg) P. berghei parasites expressing P. vivax genes were generated and used to demonstrate the protective efficacy of Ad-P PvCSP and Ad-M PvTRAP vaccines.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:581040 |
| Date | January 2012 |
| Creators | Bauza, Karolis |
| Contributors | Hill, Adrian; Reyes-Sandoval, Arturo |
| Publisher | University of Oxford |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://ora.ox.ac.uk/objects/uuid:f96234df-74fa-4461-ba2e-a3cc4f8abfa0 |
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