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Annual and Interim Progress Report Summaries

Principal Investigator: Steven Patterson

Project: Optimization and Efficacy of a Transcutaneous, “Stealth” Adenovirus Vector Vaccine for Mucosal Protection Against HIV.

 
Submitted August 31, 2012

This project aims to develop a CD8 T cell vaccine that will induce responses against multiple epitopes and overcome the problem of virus immune escape. The vaccine will be delivered to the skin, a tissue rich in dendritic cells and essential for the initiation of a T cell response, by sugar micro-needles patches containing the embedded vaccine. We have shown that the adenovirus vaccine vector in a dried sugar formulation maintains viability at high temperatures for several months and demonstrated in the mouse that the sugar patch delivery system generates good immune responses. More recently we have shown in the mouse that skin vaccination with patches induces antigen-specific CD8 responses in the genital tract that can kill target cells. We have tested two strategies to stimulate a broad cytotoxic CD8 T cell response. In the first strategy HIV gag genes have been fused with ubiquitin to more efficiently target the proteasome and increase MHC peptide complexes on the cell surface. Vaccine vectors containing these fusions have been tested and do very effectively enhance proteasomal targeting, however, although some modest increase in response to certain epitopes has been seen in vaccinated mice overall we have observed reduced immunogenicity. The second strategy designed to broaden the response is to fragment the vaccine gene and clone segments into separate vectors. The aim is to express all the potential epitopes but reduce the number of different epitopes expressed on individual dendritic cells and overcome competition between T cells recognising different epitopes, a factor thought to limit the breadth of the response. To test this hypothesis 7 SIV gag gene segments spanning the whole of gag have been cloned into Ad5 and tested in a human in vitro priming system and encouragingly, compared to the full length gag, the mini gene vectors induced a marked increase in the number of epitopes recognised. A DNA prime Ad5 boost approach has been adopted to test the new vaccines in Mauritian Cynomolgus macaques (MCM). Animals have been vaccinated intradermally with either full length unmodified gag, full length gag fused to ubiquitin or the 7 mini gene fragments each fused to ubiquitin. The limited number of MHC haplotypes expressed by these animals has enabled us to have groups of control and vaccinated animals with a similar range of MHC genetic backgrounds which will enable data to be more clearly interpreted. These animals have been challenged at 10 weekly intervals intrarectally with low doses of SIVmac 251. Vaccination induced good CD4 and CD8 responses with about 50% of CD4 cells expressing mucosal homing markers. The vaccinated groups showed statistically significant (p=0.015) resistance to challenge compared to controls. This encouraging result is the first report of vaccination with gag employing a replication defective vector that has conferred resistance to infection. Interestingly the best protection was provided by the unmodified full length gag vaccine and to test whether it is the intradermal route of vaccination that has provided protection animals have vaccinated with the unmodified full gag vaccine by the intramuscular route. Results of virus challenge for these animals will be available in November 2012 . Thus of a number of strategies that were tested two, skin vaccination and gene fragmentation, may facilitate future HIV vaccine development.

Submitted January 15, 2012
Submitted March 1, 2011
Submitted July 26, 2010
Submitted January 13, 2010 (Interim Report)
Submitted July 31, 2009
Submitted January 5, 2009 (Interim Report)
Submitted August 1, 2008 
Submitted January 15, 2008 (Interim Report)
Submitted August 1, 2007
 
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