The Evaluation of Memory T cell Responses Induced by a Novel Tuberculosis Vaccine

• Main Author: Beveridge, Natalie E. R.
• Published: University of Oxford 2007
• Subjects: 616.079
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.491319

One approach to combat the devastating infectious diseases that are HIV/AIDS, malaria and tuberculosis, is the development ofT cell vaccines which induce cell-mediated immune responses against the causative intracellular pathogens. One of the candidate tuberculosis vaccines that has been developed as such is modified vaccinia Ankara expressing antigen 85A (MVA85A). MVA85A was designed to be used in combination with the only currently licensed tuberculosis vaccine (BCG), in a prime-boost vaccination strategy (BCG prime-MYA85A boost). Early Phase I studies have shown that this approach induced a large M tuberculosis-specific lymphocyte IFNy response measured in the periphery by ex vivo ELISpot in healthy UK volunteers. The IFNy response measured was greater than that induced by immunisation with the either of the two vaccines alone (BCG or MVA85A), and was largely comprised ofCD4+ T cells. No further details regarding other characteristics of the vaccine-induced immune response had been examined. As the BCG-MVA85A vaccine strategy progresses along the clinical trial and drug development pathway it will be important to characterise the BCG-MVA85A induced Immune response in greater detail. More detailed immunological studies may provide insight into a protective or non-protective vaccine-induced immune response and help to guide the selection of future vaccine candidates. This thesis presents a detailed immunological study of the functional and phenotypic characteristics of the BCG-MVA85A induced immune response. As previously documented an impressive CD4+ T cell response was induced by BCG-MVA85A vaccination. Antigen 85A-specific CD4+ T cells were polyfunctional (they produced IFNy, TNFa, IL-2 and MIP-l~ simultaneously); relatively non-terminally differentiated and showed robust proliferative potential. These characteristics are currently thought to be important in generating effective memory T cell populations. The peak proliferative response in CD4+ T cells was found to occur six months following MVA85A boosting vaccination. In addition to CD4+ T cells, M tuberculosis-specific CD8+ and y/b T cell responses were also detected following BCG-MVA85A vaccination. Although these populations were less polyfunctional than the CD4+ T cells, their detection is noteworthy since the induction of a multifaceted immune response by vaccination is highly likely to be advantageous in providing protection against tuberculosis disease. A comparison of IFNy detection methods revealed that future immunological studies should ideally include a combination of ex vivo and cultured assays, along with PBMC and whole blood based methods to ensure a thorough and multi-faceted evaluation of the immune response is achieved. In summary, the data presented in this thesis have provided novel insights into the multicomponent response profile of BCG-MVA85A in healthy individuals. Although it remains to be seen whether this profile represents a protective immune response, these data do support the continued development ofMVA85A as a novel tuberculosis vaccine.