Technical and regulatory hurdles for DNA vaccines

Donnelly, John; Berry, Karin Zemski; Ulmer, Jeffrey B.

doi:10.1016/s0020-7519(03)00056-0

Cited by 113 publications

(58 citation statements)

References 119 publications

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“…4 However, thus far, DNA vaccines have shown low immunogenicity when tested on large animals and humans. 5 There is a need for strategies that can enhance the immunogenicity elicited by DNA vaccines expressing the antigens of interest. The potency of a DNA vaccine in terms of eliciting an effective immune response is associated with the levels the encoded proteins in eukaryotic cells.…”

mentioning

confidence: 99%

MIDGE/hNIS vaccination generates antigen‐associated CD8⁺IFN‐γ⁺ T cells and enhances protective antitumor immunity

Choi¹,

Jeon²,

Kang³

et al. 2007

Intl Journal of Cancer

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Human sodium iodide symporter (hNIS) is a transmembrane protein that actively transports iodide ions into thyroid cells. hNIS is over-expressed in some cases of the thyroid cancers compared with the surrounding normal tissues and has been considered to be an attractive target for immunotherapy. The aim of this study is to determine the feasibility of utilizing the hNIS antigenic protein in enhanced-antigen-associated immunotherapy using image analysis with a gamma counter. To accomplish this, minimalistic immunogenically defined gene expression (MIDGE), either plain or coupled to a nuclear localization signal (NLS) peptide, was used as a vector system. Vaccination with MIDGE/hNIS, MIDGE/ hNIS-NLS and pcDNA3.1/hNIS produced a significant increase in the number of hNIS-associated IFN-c-secreting CD8 1 T cells, with MIDGE/hNIS having the strongest effect. In addition, immunization with the hNIS encoding vectors induced antigen-mediated antitumor activity against NIS-expressing CT26 tumors in vivo, with the highest tumor free rate (100%) and lowest tumor growth being observed up to 40 days after the CT26/NIS tumor challenge with MIDGE/hNIS than those resulting from other immunization groups. Tumor progression could be followed noninvasively and repetitively by monitoring levels of hNIS gene expression in the tumors using scintigraphic image analysis. Overall, hNIS has a potential use as an antigen for immunization approaches, and vaccination with MIDGE/hNIS vectors is an effective means of generating hNIS-associated immune responses in mice. ' 2007 Wiley-Liss, Inc.

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mentioning

confidence: 99%

MIDGE/hNIS vaccination generates antigen‐associated CD8⁺IFN‐γ⁺ T cells and enhances protective antitumor immunity

Choi¹,

Jeon²,

Kang³

et al. 2007

Intl Journal of Cancer

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“…Immunotherapies based on cancer DNA vaccines generate cancer-specific immunity by inducing Th1 or Th2 immune response [2,11]. However, tumor cells can escape immune systems augmented by immunotherapies by not expressing MHC class molecules or antigens.…”

Section: Discussionmentioning

confidence: 99%

CpG Oligodeoxynucleotides Enhance the Activities of CD8+ Cytotoxic T-Lymphocytes Generated by Combined hMUC1 Vaccination and hNIS Radioiodine Gene Therapy

Jeon

Choi

Lee

et al. 2010

Nucl Med Mol Imaging

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Purpose The authors evaluated whether the cytotoxicity of CD8+CTLs generated by combined hMUC1 vaccination and hNIS radioiodine gene therapy was enhanced in the presence of CpG in an established tumor model. Methods CMNF cells (CT26 cells expressing hMUC1, hNIS and Firefly luciferase) were transplanted into BALB/c mice. Four and 10 days later, tumor-bearing mice were immunized intramuscularly with pcDNA3.1 or pcDNA-hMUC1 or pcDNA-hMUC1+CpG, and subsequently administered PBS or 131 I [five groups (seven mice/group): referred to as the pcDNA3.1+PBS, phMUC1+PBS, pcDNA3.1+ 131 I, phMUC1+ 131 I, and phMUC1+ 131 I+CpG groups]. The number of CD8+IFNr+ T cells of splenocytes as well as the number of CD8+IFNr+ T cells of splenocytes re-stimulated with CD11c+ cells was determined using FACS analysis. The activities of cytotoxic T cells (CTLs) from splenocytes were investigated.Results Marked tumor growth inhibition was observed in the phMUC1+ 131 I and phMUC1+ 131 I+CpG groups, but not in the other three single therapy groups. Particularly the number of CD8+IFN-γ+ T cells of splenocytes was more increased in the phMUC1+ 131 I+CpG group than in the phMUC1+ 131 I group. The number of CD8+IFN-γ+ T cells of splenocytes stimulated with CD11c+ cells was the most enhanced in the phMUC1+ 131 I+CpG group among the five groups. Concurrently, the activities of hMUC1-associated CTLs obtained from splenocytes in the phMUC1+ 131 I+CpG group were significantly greater than in the other four groups (pcDNA+PBS, phMUC1+PBS, pcDNA+ 131 I, phMUC1+ 131 I, and phMUC1+ 131 I+CpG, 16±2%, 20±1%, 30±2%, 60±2%, and 87±2%, respectively, P<0.01). Conclusion Our data suggest that adjuvant CpG ODNs can increase the killing activities of CTLs generated by combined hMUC1 DNA vaccination and hNIS radioiodine gene therapy.

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“…These approaches combine the ability to provide sufficient immunostimulation, as well as targeting of CD8 ϩ T cell immunity. Of these approaches, live vectors come with the risk of reconversion to virulence (53) and DNA vaccines often require either high doses or special delivery approaches for sustained immunity (54). Liposomes composed of conventional ester lipids have been considered for T cell vaccine development, but often require a codelivered immunostimulant for sufficient augmentation of innate immunity (55,56).…”

Section: Discussionmentioning

confidence: 99%

Rapid Clonal Expansion and Prolonged Maintenance of Memory CD8+ T Cells of the Effector (CD44highCD62Llow) and Central (CD44highCD62Lhigh) Phenotype by an Archaeosome Adjuvant Independent of TLR2

Krishnan

Gurnani

Dicaire

et al. 2007

The Journal of Immunology

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Vaccines capable of eliciting long-term T cell immunity are required for combating many diseases. Live vectors can be unsafe whereas subunit vaccines often lack potency. We previously reported induction of CD8+ T cells to Ag entrapped in archaeal glycerolipid vesicles (archaeosomes). In this study, we evaluated the priming, phenotype, and functionality of the CD8+ T cells induced after immunization of mice with OVA-Methanobrevibacter smithii archaeosomes (MS-OVA). A single injection of MS-OVA evoked a profound primary response but the numbers of H-2KbOVA257–264-specific CD8+ T cells declined by 14–21 days, and <1% of primarily central phenotype (CD44highCD62Lhigh) cells persisted. A booster injection of MS-OVA at 3–11 wk promoted massive clonal expansion and a peak effector response of ∼20% splenic/blood OVA257–264-specific CD8+ T cells. Furthermore, contraction was protracted and the memory pool (IL-7Rαhigh) of ∼5% included effector (CD44highCD62Llow) and central (CD44highCD62Lhigh) phenotype cells. Recall response was observed even at >300 days. CFSE-labeled naive OT-1 (OVA257–264 TCR transgenic) cells transferred into MS-OVA-immunized recipients cycled profoundly (>90%) within the first week of immunization indicating potent Ag presentation. Moreover, ∼25% cycling of Ag-specific cells was seen for >50 days, suggesting an Ag depot. In vivo, CD8+ T cells evoked by MS-OVA killed >80% of specific targets, even at day 180. MS-OVA induced responses similar in magnitude to Listeria monocytogenes-OVA, a potent live vector. Furthermore, protective CD8+ T cells were induced in TLR2-deficient mice, suggesting nonengagement of TLR2 by archaeal lipids. Thus, an archaeosome adjuvant vaccine represents an alternative to live vectors for inducing CD8+ T cell memory.

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Technical and regulatory hurdles for DNA vaccines

Cited by 113 publications

References 119 publications

MIDGE/hNIS vaccination generates antigen‐associated CD8⁺IFN‐γ⁺ T cells and enhances protective antitumor immunity

MIDGE/hNIS vaccination generates antigen‐associated CD8⁺IFN‐γ⁺ T cells and enhances protective antitumor immunity

CpG Oligodeoxynucleotides Enhance the Activities of CD8+ Cytotoxic T-Lymphocytes Generated by Combined hMUC1 Vaccination and hNIS Radioiodine Gene Therapy

Rapid Clonal Expansion and Prolonged Maintenance of Memory CD8+ T Cells of the Effector (CD44highCD62Llow) and Central (CD44highCD62Lhigh) Phenotype by an Archaeosome Adjuvant Independent of TLR2

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Technical and regulatory hurdles for DNA vaccines

Cited by 113 publications

References 119 publications

MIDGE/hNIS vaccination generates antigen‐associated CD8+IFN‐γ+ T cells and enhances protective antitumor immunity

MIDGE/hNIS vaccination generates antigen‐associated CD8+IFN‐γ+ T cells and enhances protective antitumor immunity

CpG Oligodeoxynucleotides Enhance the Activities of CD8+ Cytotoxic T-Lymphocytes Generated by Combined hMUC1 Vaccination and hNIS Radioiodine Gene Therapy

Rapid Clonal Expansion and Prolonged Maintenance of Memory CD8+ T Cells of the Effector (CD44highCD62Llow) and Central (CD44highCD62Lhigh) Phenotype by an Archaeosome Adjuvant Independent of TLR2

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MIDGE/hNIS vaccination generates antigen‐associated CD8⁺IFN‐γ⁺ T cells and enhances protective antitumor immunity

MIDGE/hNIS vaccination generates antigen‐associated CD8⁺IFN‐γ⁺ T cells and enhances protective antitumor immunity