Phase 1 Safety and Immunogenicity Evaluation of a Multiclade HIV‐1 DNA Candidate Vaccine

Fred Hutchinson Cancer Research Center, Seattle, Washington, United States
The Journal of Infectious Diseases (Impact Factor: 6). 01/2007; 194(12):1650-60. DOI: 10.1086/509259
Source: PubMed


Gene-based vaccine delivery is an important strategy in the development of a preventive vaccine for acquired immunodeficiency syndrome (AIDS). Vaccine Research Center (VRC) 004 is the first phase 1 dose-escalation study of a multiclade HIV-1 DNA vaccine.
VRC-HIVDNA009-00-VP is a 4-plasmid mixture encoding subtype B Gag-Pol-Nef fusion protein and modified envelope (Env) constructs from subtypes A, B, and C. Fifty healthy, uninfected adults were randomized to receive either placebo (n=10) or study vaccine at 2 mg (n=5), 4 mg (n=20), or 8 mg (n=15) by needle-free intramuscular injection. Humoral responses (measured by enzyme-linked immunosorbant assay, Western blotting, and neutralization assay) and T cell responses (measured by enzyme-linked immunospot assay and intracellular cytokine staining after stimulation with antigen-specific peptide pools) were measured.
The vaccine was well tolerated and induced cellular and humoral responses. The maximal CD4(+) and CD8(+) T cell responses occurred after 3 injections and were in response to Env peptide pools. The pattern of cytokine expression by vaccine-induced HIV-specific T cells evolved over time, with a diminished frequency of interferon- gamma -producing T cells and an increased frequency of interleukin-2-producing T cells at 1 year.
DNA vaccination induced antibody to and T cell responses against 3 major HIV-1 subtypes and will be further evaluated as a potential component of a preventive AIDS vaccine regimen.

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    • "DNA vaccine expressing gp120 and Gag, followed by QS21- adjuvanted polyvalent gp120 protein boost (DP6-001 study) in which multifunctional T cells and high-titre gp120-specific binding and broadly-neutralizing antibodies as well as ADCC were induced (Graham et al., 2006; Bansal et al., 2008; Wang et al., 2008b; Vaine et al., 2010). Apart from effective delivery strategies and routes of immunization , there is evidence showing that expression of DNA vaccines and subsequent immunogenicity in humans and other primates can be limited by serum amyloid P component (SAP), a protein found in blood and known to bind strongly to DNA (Wang et al., 2011, 2012). "
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    • "Even though specific antibody and CTL responses could be induced in clinical trials with naked DNA vaccines, by the intramuscular or intradermal route, high doses of DNA were necessary to elicit detectable immune responses [89] [90]. Large quantities, that is, 5–10 mg, are required to induce only modest immunogenicity [91]. Modifying the microenvironment of the vaccinated site by coadministration of genetic, that is, DNA plasmids coding for immunostimulatory molecules, protein, or chemical adjuvants, improves the low immunogenicity of DNA vaccines [31]. "
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    ABSTRACT: Due to their rapid and widespread development, DNA vaccines have entered into a variety of human clinical trials for vaccines against various diseases including cancer. Evidence that DNA vaccines are well tolerated and have an excellent safety profile proved to be of advantage as many clinical trials combines the first phase with the second, saving both time and money. It is clear from the results obtained in clinical trials that such DNA vaccines require much improvement in antigen expression and delivery methods to make them sufficiently effective in the clinic. Similarly, it is clear that additional strategies are required to activate effective immunity against poorly immunogenic tumor antigens. Engineering vaccine design for manipulating antigen presentation and processing pathways is one of the most important aspects that can be easily handled in the DNA vaccine technology. Several approaches have been investigated including DNA vaccine engineering, co-delivery of immunomodulatory molecules, safe routes of administration, prime-boost regimen and strategies to break the immunosuppressive networks mechanisms adopted by malignant cells to prevent immune cell function. Combined or single strategies to enhance the efficacy and immunogenicity of DNA vaccines are applied in completed and ongoing clinical trials, where the safety and tolerability of the DNA platform are substantiated. In this review on DNA vaccines, salient aspects on this topic going from basic research to the clinic are evaluated. Some representative DNA cancer vaccine studies are also discussed.
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    • "Even with breakthroughs in finding conserved epitopes, I doubt that we can escape totally from having to make multivalent or regional HIV vaccines [45]. Indeed, recent reports suggest that multivalent HIV envelopes do give broad neutralizing responses [46-49]. "
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