Introduction: In 2010, 1.4 million people died from tuberculosis. Bacille Calmette Guerin (BCG) is the only vaccine against tuberculosis that is available, but it has variable efficacy around the world. There is not only an urgent need for a new vaccine, but also identification of a correlate of protection and/or biomarker of disease to enable rapid progression of efficacious and safe vaccine candidates into the clinic. Methods: In order to identify correlates of protection or biomarkers of disease, mycobacteria-specific lymphoproliferation was measured by thymidine incorporation, T cell kinetics were evaluated using a no-wash whole blood flow cytometric approach and cytokine secretion was measured by intracellular cytokine staining. These approaches were used to measure immune responses in rhesus macaques (RM) vaccinated with BCG or BCG/MVA85A and subsequently challenged with M. tuberculosis, and responses in RM and cynomolgus macaques of Mauritian (MCM) and Chinese origin (CCM) after infection with M. tuberculosis. Results: Proliferative and cytokine responses were detected after vaccination, but these responses did not correlate with protection following challenge. Animals that were unable to control disease progression had C!. decline in the number of lymphocytes and T cells and an increase in granulocytes in the periphery. A decline in lymphocyte proliferative capacity and a higher proportion of IFNy-producing T cells after infection was also observed in animals that developed severe disease symptoms. Higher proliferative and IFNy-secreting T cells were observed in RM compared to MCM or CCM and there were also intrinsic differences in white blood cell and T cell numbers between the groups of macaques of different origin and those differences remained after challenge with M. tuberculosis. Conclusion: Studies performed during this research degree confirm that measurement of IFNy-producing T cells, lymphocyte proliferation and polyfunctional T cells does not provide a correlate of protection. However, a decline in lymphocyte and T cell numbers, an increase in granulocytes, a decline in lymphocyte proliferation and increase in IFNy-producing T cells early after infection are biomarkers of disease progression.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:577995 |
| Date | January 2012 |
| Creators | Gooch, Karen Elizabeth |
| Publisher | Open University |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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