Abstract
An effective vaccine against HIV-1 is generally considered the best hope for controlling the raging AIDS pandemic. As a part of our AIDS vaccine development effort, we constructed a dual-promoter plasmid capable of high-level expression of 2 independent transgenes. HIV-1 gag, pol, env, nef, and tat from a primary subtype C/B' CCR5-tropic HIV-1 were "codon" optimized, modified to eliminate known functional activity, and assembled using an overlapping polymerase chain reaction into 2 plasmids: ADVAX-I (containing env and gag) and ADVAX-II (containing pol and nef-tat). These 2 dual-promoter candidate vaccines showed levels of HIV-1 gene expression comparable to those observed with single-gene plasmids in vitro. Importantly, immunization of mice with these vaccine constructs resulted in dose-dependent multigenic CD4 and CD8 T-cell responses equivalent to those provided by vaccination with single-gene plasmids. With input from the US Food and Drug Administration, ADVAX-I and ADVAX-II have since been combined as a single candidate DNA vaccine, ADVAX. A phase 1 clinical trial of this product has been successfully completed, and its use in prime-boost studies is now underway.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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AIDS Vaccines / administration & dosage
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AIDS Vaccines / genetics
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AIDS Vaccines / immunology
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Animals
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Blotting, Western
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CD4-Positive T-Lymphocytes / cytology
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CD4-Positive T-Lymphocytes / immunology
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CD8-Positive T-Lymphocytes / cytology
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CD8-Positive T-Lymphocytes / immunology
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Cell Line
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Cloning, Molecular
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Enzyme-Linked Immunosorbent Assay
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Gene Products, env / genetics
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Gene Products, env / immunology
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Gene Products, env / metabolism
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Gene Products, gag / genetics
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Gene Products, gag / immunology
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Gene Products, gag / metabolism
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Gene Products, nef / genetics
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Gene Products, nef / immunology
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Gene Products, nef / metabolism
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Gene Products, pol / genetics
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Gene Products, pol / immunology
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Gene Products, pol / metabolism
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Gene Products, tat / genetics
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Gene Products, tat / immunology
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Gene Products, tat / metabolism
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HIV Antibodies / blood
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HIV-1 / genetics
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HIV-1 / immunology*
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Humans
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Immunization / methods
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Interferon-gamma / metabolism
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Mice
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Plasmids / genetics
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Promoter Regions, Genetic / genetics*
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Retroviridae Proteins / genetics*
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Retroviridae Proteins / immunology
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Retroviridae Proteins / metabolism
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Spleen / cytology
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Spleen / immunology
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Spleen / metabolism
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Transfection
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Vaccines, DNA / administration & dosage
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Vaccines, DNA / genetics
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Vaccines, DNA / immunology*
Substances
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AIDS Vaccines
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Gene Products, env
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Gene Products, gag
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Gene Products, nef
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Gene Products, pol
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Gene Products, tat
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HIV Antibodies
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Retroviridae Proteins
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Vaccines, DNA
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Interferon-gamma