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.

1 Follower
12 Reads
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Development of an effective HIV/AIDS vaccine remains a big challenge, largely due to the enormous HIV diversity which propels immune escape. Thus novel vaccine strategies are targeting multiple variants of conserved antibody and T cell epitopic regions which would incur a huge fitness cost to the virus in the event of mutational escape. Besides immunogen design, the delivery modality is critical for vaccine potency and efficacy, and should be carefully selected in order to not only maximize transgene expression, but to also enhance the immuno-stimulatory potential to activate innate and adaptive immune systems. To date, five HIV vaccine candidates have been evaluated for efficacy and protection from acquisition was only achieved in a small proportion of vaccinees in the RV144 study which used a canarypox vector for delivery. Conversely, in the STEP study (HVTN 502) where human adenovirus serotype 5 (Ad5) was used, strong immune responses were induced but vaccination was more associated with increased risk of HIV acquisition than protection in vaccinees with pre-existing Ad5 immunity. The possibility that pre-existing immunity to a highly promising delivery vector may alter the natural course of HIV to increase acquisition risk is quite worrisome and a huge setback for HIV vaccine development. Thus, HIV vaccine development efforts are now geared toward delivery platforms which attain superior immunogenicity while concurrently limiting potential catastrophic effects likely to arise from pre-existing immunity or vector-related immuno-modulation. However, it still remains unclear whether it is poor immunogenicity of HIV antigens or substandard immunological potency of the safer delivery vectors that has limited the success of HIV vaccines. This article discusses some of the promising delivery vectors to be harnessed for improved HIV vaccine efficacy.
    Frontiers in Microbiology 08/2014; 5(439):439. DOI:10.3389/fmicb.2014.00439 · 3.99 Impact Factor
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    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.
    BioMed Research International 03/2010; 2010(938):174378. DOI:10.1155/2010/174378 · 2.71 Impact Factor
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Since the announcement of the STEP trial results in the past months, we have heard many sober pronouncements on the possibility of an HIV vaccine. On the other hand, optimistic quotations have been liberally used, from Shakespeare's Henry V's "Once more unto the breach, dear friends" to Winston Churchill's definition of success as "going from one failure to another with no loss of enthusiasm". I will forgo optimistic quotations for the phrase "Sang Froid", which translates literally from the French as "cold blood"; what it really means is to avoid panic when things look bad, to step back and coolly evaluate the situation. This is not to counsel easy optimism or to fly in face of the facts, but I believe that while the situation is serious, it is not desperate. I should stipulate at the outset that I am neither an immunologist nor an expert in HIV, but someone who has spent his life in vaccine development. What I will try to do is to provide a point of view from that experience. There is no doubt that the results of STEP were disappointing: not only did the vaccine fail to control viral load, but may have adversely affected susceptibility to infection. But HIV is not the only vaccine to experience difficulties; what lessons can we glean from prior vaccine development?
    Journal of the International AIDS Society 03/2009; 12(1):2. DOI:10.1186/1758-2652-12-2 · 5.09 Impact Factor
Show more

Preview (2 Sources)

12 Reads
Available from