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• W20685038 abstract "Thirty six million people, worldwide, are now infected with the human immunodeficiency virus (HIV). The vast majority of HIV infections occur in developing nations and tragically, in most developing nations the rate of HIV infection continues to rise. A vaccine is desperately needed to prevent the continued spread of HIV. Compelling evidence suggests that cytotoxic T lymphocytes (CTL) have an important role in preventing HIV infection and/or slowing the progression to AIDS. Emerging evidence suggests that an HIV vaccine that induces CTL at mucosal surfaces might be most effective at preventing the sexual transmission of HIV. This thesis describes the in-vitro analysis and pre-clinical testing of an HIV polytope vaccine in mice. PolytopeTM vaccines consist of multiple conjoined CTL epitopes combined into a single artificial gene that can be delivered by attenuated viral or bacterial vectors or DNA immunisation plasmids. The immunogenicity of an HIV polytope vaccine that comprised seven contiguous minimal HLA A2-restricted CTL epitopes from five HIV antigens was evaluated using human CTL lines and HLA A2 transgenic mice. Epitope specific CTL lines derived from HIV-infected individuals were able to recognise every epitope within the polytope construct. In addition, HLA A2-transgenic mice immunised with a recombinant vims vaccine encoding the HIV polytope generated CTL responses specific for multiple epitopes. Each epitope in the polytope construct was therefore processed and presented, illustrating the feasibility of the polytope approach for HIV vaccine design. By simultaneously inducing CTL specific for different epitopes, an HIV polytope vaccine might generate activity against multiple challenge isolates and/or preempt the expansion of CTL escape mutants. Emerging evidence suggests that an HIV vaccine may need to elicit immune responses at mucosal surfaces to prevent the sexual transmission of HIV. Mucosal immunity is believed to be most effectively generated by delivering vaccines directly to mucosal surfaces. The ability of Salmonella to induce protective CTL responses was investigated using two strategies; S. typhimurium mediated antigen delivery where influenza NP was expressed by the bacteria and secondly, S. typhimurium mediated DNA vaccine delivery where polytope immunogen was expressed using a eukaryotic promoter. In the first strategy, S. typhimurium mediated antigen delivery vaccines conferred protection against a mucosal vaccinia challenge. This protection was enhanced when E.coli hemolysin genes (hlyCABD) were co-expressed by the bacteria. These genes were postulated to enhance bacterial endosome escape and thereby improve the delivery of vaccine antigen to the cell cytoplasm. The second strategy, evaluating S. typhimurium polytope DNA vaccine delivery, elicited multiple CTL responses that conferred protection against a mucosal vaccinia challenge. A S. typhimurium Dasd mutant that was incapable of completing synthesis of the bacterial cell wall in-vivo, improved CTL induction and protection mediated by the S. typhimurium delivered DNA vaccine. The in-vivo lysis of this strain was postulated to enhance the delivery of DNA to the cell cytoplasm due to bacterial lysis within antigen presenting cells. This represents one of the first reported demonstrations of mucosal delivery of polytope vaccines. However, the weak responses and requirement for multiple immunisations suggested that Salmonella enterica vaccines will require further optimisation before being suitable as an HIV vaccine vector for human use. A difficulty associated with HIV CTL vaccine development is that relatively few vaccine strategies exist that safely and effectively induce CTL in humans. DNA vaccines represent a promising vaccine strategy, however, DNA immunisations so far have elicited relatively weak CTL responses in humans. Prime and boost vaccine approaches consisting of a DNA prime immunisation followed by an attenuated poxvirus boost immunisation have generated effective CTL-based protection against retroviral challenge in non-human primates. To better understand the principles that underpin the success of the DNA prime poxvirus boost strategy various DNA, peptide and modified vaccinia Ankara (MVA) combinations were compared for their ability to induce CTL and protect mice from challenge with influenza. No evidence was obtained to support a role for the induction of high avidity CTL or the avoidance of vector responses as important features of prime and boost immunisation. Evidence was obtained to indicate that the DNA prime immunisation may be important for producing enhanced Th 1 bias in the resulting CTL. This observation may contribute to the development of effective vaccine strategies that use a single delivery modality." @default.
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• W20685038 date "2002-01-01" @default.
• W20685038 modified "2023-09-27" @default.
• W20685038 title "Development of a mucosal HIV polytope vaccine" @default.
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