Vaccination continues to represent the most effective means of providing immunological protection against infectious disease in human populations. With the World Health Organisation (WHO) reporting over 1.2 million AIDS related deaths in 2014, an efficacious HIV1 vaccine is urgently needed. The UCT Human Immunodeficiency Virus (HIV) Vaccine Development Group has focussed on understanding novel HIV-1 vaccine vectors, such as modified BCG, combined with modified vaccinia Ankara in the context of heterologous prime boost regimes. The tuberculosis vaccine Bacillus Calmette–Guérin (BCG) has a wellestablished safety profile as well as notable adjuvant activity with an estimated 3 billion doses administered globally since 1921. The development of modern molecular biology techniques in recent times has led to the creation of modified strains of BCG which have been shown in many cases to be safer and/or more immunogenic than the wild type strains in terms of delivering heterologous antigen. This study focuses on exploiting and combining two particular strategies of rBCG modification. The first is the development of auxotrophic strains that contain deletions geared towards preventing the bacteria from synthesising essential growth compounds or amino acids. An example of this is the ΔpanCD auxotroph of rBCG which does not synthesise pantothenic acid and thus has limited intracellular replication leading to less pathology. The UCT group has previously reported that HIV vaccines vectored by the Pasteur strain of rBCG ΔpanCD induced less pathology but improved immunogenicity as compared to Pasteur WT in the murine model (when used a prime in conjunction with an MVA boost). A second notable BCG modification strategy is the inclusion of exogenous genes to improve the immunogenicity of rBCG as a vaccine vector. An example of this is the insertion of the detoxified Clostridium perfringens toxin, perfringolysin O (pfo), into the rBCG genome. Upon expression, pfo forms pores in the endosome which facilitates translocation of vaccine derived antigen into the cytoplasm. This modification has been shown to lead to cross priming of T cells and improve the induction of vaccine specific CD8+ T cell as compared to controls.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:uct/oai:localhost:11427/22749 |
| Date | January 2016 |
| Creators | Chetty, Shivan |
| Contributors | Williamson, Anna-Lise, Chapman, Rosamund |
| Publisher | University of Cape Town, Faculty of Health Sciences, Division of Virology |
| Source Sets | South African National ETD Portal |
| Language | English |
| Detected Language | English |
| Type | Doctoral Thesis, Doctoral, PhD |
| Format | application/pdf |
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