Article

A rapid and potent DNA vaccination strategy defined by in vivo monitoring of antigen expression

Johns Hopkins University, Baltimore, Maryland, United States
Nature Medicine (Impact Factor: 28.05). 09/2005; 11(8):899-904. DOI: 10.1038/nm1264
Source: PubMed

ABSTRACT Induction of immunity after DNA vaccination is generally considered a slow process. Here we show that DNA delivery to the skin results in a highly transient pulse of antigen expression. Based on this information, we developed a new rapid and potent intradermal DNA vaccination method. By short-interval intradermal DNA delivery, robust T-cell responses, of a magnitude sufficient to reject established subcutaneous tumors, are generated within 12 d. Moreover, this vaccination strategy confers protecting humoral immunity against influenza A infection within 2 weeks after the start of vaccination. The strength and speed of this newly developed strategy will be beneficial in situations in which immunity is required in the shortest possible time.

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    • "The fusion with TTFC was shown to be critical to overcome the observed loss in immunogenicity resulting from the gene-shuffling procedure. When applied via DNA tattooing [24], TTFC-E6SH and TTFC-E7SH encoding DNA vaccines induced strong E6 and E7 specific T-cell immunity in mice. Because of these promising pre-clinical data, we are now planning to evaluate these vaccines in patients suffering from HPV16 induced malignancies. "
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    ABSTRACT: Persistent infection with high-risk human papillomaviruses (hrHPV) can result in the formation of anogenital cancers. As hrHPV proteins E6 and E7 are required for cancer initiation and maintenance, they are ideal targets for immunotherapeutic interventions. Previously, we have described the development of DNA vaccines for the induction of HPV16 E6 and E7 specific T cell immunity. These vaccines consist of 'gene-shuffled' (SH) versions of HPV16 E6 and E7 that were fused to Tetanus Toxin Fragment C domain 1 (TTFC) and were named TTFC-E6SH and TTFC-E7SH. Gene-shuffling was performed to avoid the risk of inducing malignant transformation at the vaccination site. Here, we describe the preclinical safety evaluation of these candidate vaccines by analysis of their transforming capacity in vitro using established murine fibroblasts (NIH 3T3 cells) and primary human foreskin keratinocytes (HFKs). We demonstrate that neither ectopic expression of TTFC-E6SH and TTFC-E7SH alone or in combination enabled NIH 3T3 cells to form colonies in soft agar. In contrast, expression of HPV16 E6WT and E7WT alone or in combination resulted in effective transformation. Similarly, retroviral transduction of HFKs from three independent donors with both TTFC-E6SH and TTFC-E7SH alone or in combination did not show any signs of immortalization. In contrast, the combined expression of E6WT and E7WT induced immortalization in HFKs from all donors. Based on these results we consider it justified to proceed to clinical evaluation of DNA vaccines encoding TTFC-E6SH and TTFC-E7SH in patients with HPV16 associated (pre)malignancies.
    Vaccine 04/2012; 30(28):4259-66. DOI:10.1016/j.vaccine.2012.04.013 · 3.49 Impact Factor
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    • "Highfrequency oscillating tattoo needles can pierce the skin to deliver vaccine in the dermis. DNA tattooing induced better humoral and cellular immune responses than intramuscular immunization in animal studies (Bins et al. 2005). "
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    ABSTRACT: The skin is known to be a highly immunogenic site for vaccination, but few vaccines in clinical use target skin largely because conventional intradermal injection is difficult and unreliable to perform. Now, a number of new or newly adapted delivery technologies have been shown to administer vaccine to the skin either by non-invasive or minimally invasive methods. Non-invasive methods include high-velocity powder and liquid jet injection, as well as diffusion-based patches in combination with skin abrasion, thermal ablation, ultrasound, electroporation, and chemical enhancers. Minimally invasive methods are generally based on small needles, including solid microneedle patches, hollow microneedle injections, and tattoo guns. The introduction of these advanced delivery technologies can make the skin a site for simple, reliable vaccination that increases vaccine immunogenicity and offers logistical advantages to improve the speed and coverage of vaccination.
    02/2011; 1(1):7-12. DOI:10.1007/s13346-010-0005-z
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    • "Therefore, delivery methods that allow efficient immunization without adjuvants are highly desir- able. For DNA vaccination, tattooing has been shown to induce higher cellular and humoral immune responses than intramuscular needle injection [11] [12]. The tattoo procedure causes many minor mechanical injuries followed by hemorrhage, necrosis, inflammation, and regeneration of the skin and thus non-specifically stimulates the immune system [13]. "
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