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305 The Multi-Epitope Approach to Development of HIV Vaccines
M. Newman*, B. Livingston, D. McKinney, R. Chesnut, and A. Sette
Epimmune Inc., San Diego, CA, USA
Background: The use of defined, minimal cytotoxic (CTL) and helper T-lymphocyte (HTL) epitopes in vaccines has several advantages that are well suited for HIV. First, it is possible to use epitopes that are conserved, thus targeting majority of viral variants within a given clade or across clades. Second, epitopes from multiple viral structural or accessory genes can be included in vaccines, which supports the induction cellular immune responses with significant breadth. Finally, dominance relationships between epitopes can be altered to increase immune recognition of subdominant epitopes.
Methods: Two experimental vaccines based on either CTL or HTL epitopes were produced as DNA plasmid vaccines. The CTL vaccine contains 21 epitopes restricted in a supertype manner to HLA-A2, -A3, and -B7. This vaccine is predicted to be immunogenic in approximately 85% of the population, regardless of ethnic background. The HTL vaccine is composed of 18 epitopes restricted to the 2 known HLA-DR supertypes and it is predicted to be highly immunogenic in 100% of the population. The vaccines include targeting sequences to direct the encoded gene products to different cellular compartment and amino acid spacer sequences between epitopes to optimize the processing and subsequent presentation of the individual epitopes.
Results: These vaccines are immunogenic in HLA transgenic mice, inducing CTL or HTL responses to multiple epitopes after a single immunization. The immunogenicity of the CTL vaccine was augmented significantly through the use of spacers to optimize proteosomal processing, whereas the potency of HTL vaccine benefited from intracellular targeting of the epitopes to the lysosome compartments.
Conclusions: Data from these studies demonstrate the immunogenicity of CTL and HTL epitope-based vaccines and methods for increasing their immunogenicity. Vaccines based on either CTL or HTL epitopes will be developed and evaluated in clinical trials, individually and together, to determine their potential utility as therapeutic and prophylactic products.
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