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9 Development of a Synthetic Scrambled Antigen Vaccine (SAVINE) Designed for Global Use That Includes All HIV-1 Proteins
S. A. Thomson*1, M. Shoobridge1, A. B. Jaramillo2, S. Kent3, R. A. Ffrench2 and I. A. Ramshaw1
1JCSMR, Australian Natl. Univ., ACT, Australia; 2Westfield Res. Labs., Sydney Children’s Hosp., NSW, Australia; and 3Dept. Micro. Immunol., Univ. of Melbourne, VIC, Australia
Background: There is increasing evidence that strong, HIV-specific T-cell responses may protect against HIV infection. However, development of a safe and effective vaccine has been slow because of the number of HIV-1 strains, the capacity of the virus to mutate and the need to cover the HLA polymorphism in the human population. We have developed a novel vaccine, in which all of the coding regions of an HIV-1 consensus sequence are incorporated in such a way that the protein functions are destroyed while still retaining the majority of CD8 and CD4 T-cell epitopes.
Methods: An HIV-1 consensus sequence designed by ranking the strain consensus sequences in the Los Alamos HIV database as follows, A/E-C-B-D-rest, was separated into overlapping fragments and randomly scrambled to design 3 novel proteins. Three synthetic cDNAs were designed, constructed, and inserted into DNA and recombinant poxvirus vaccine vectors (VV and FPV). A second set of constructs was also made containing 352 AA mutations common in the major HIV-1 strains. The HIV-1 Savine constructs were used to immunise mice by the “prime-boost” delivery strategy, boost responses in preimmune macaques, or restimulate PBMC from HIV-1-infected patients.
Results: In mice, the HIV-1 SAVINE generated CTL responses in C57BL6 mice recognising Gag and Nef. In preimmune macaques, ELISPOT assays showed that both CD8+ and CD4+ T-cell responses were boosted in vivo. In PBMCs from HIV-1-infected patients the HIV-1 SAVINE was able to restimulate both CD8+ and CD4+ HIV-1 responses as measured by CFSE staining and FACs analysis for CD4+ cells and by CTL lysis assays against recombinant VV-infected target cells. Preliminary evidence suggests some benefit combining the mutated HIV-1 savine constructs.
Conclusions: Together the data provide preliminary evidence that this vaccine may provide extremely broad T-cell immunity. We envisage that this HIV-1 vaccine candidate may find utility in diverse human populations and be effective against multiple strains of HIV-1.
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