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Vector Design for Improved DNA Vaccine Efficacy, Safety and Production.

Williams JA - Vaccines (Basel) (2013)

Bottom Line: Innovations such as electroporation, needle free jet delivery and lipid-based carriers increase transgene expression and immunogenicity through more effective gene delivery.These next generation vectors also address potential safety issues such as antibiotic selection, and increase plasmid manufacturing quality and yield in exemplary fermentation production processes.Application of optimized constructs in combination with improved delivery platforms tangibly improves the prospect of successful application of DNA vaccination as prophylactic vaccines for diverse human infectious disease targets or as therapeutic vaccines for cancer and allergy.

View Article: PubMed Central - PubMed

Affiliation: Nature Technology Corporation/Suite 103, 4701 Innovation Drive, Lincoln, NE 68521, USA. jim@natx.com.

ABSTRACT
DNA vaccination is a disruptive technology that offers the promise of a new rapidly deployed vaccination platform to treat human and animal disease with gene-based materials. Innovations such as electroporation, needle free jet delivery and lipid-based carriers increase transgene expression and immunogenicity through more effective gene delivery. This review summarizes complementary vector design innovations that, when combined with leading delivery platforms, further enhance DNA vaccine performance. These next generation vectors also address potential safety issues such as antibiotic selection, and increase plasmid manufacturing quality and yield in exemplary fermentation production processes. Application of optimized constructs in combination with improved delivery platforms tangibly improves the prospect of successful application of DNA vaccination as prophylactic vaccines for diverse human infectious disease targets or as therapeutic vaccines for cancer and allergy.

No MeSH data available.


Related in: MedlinePlus

Molecular mechanisms of DNA vaccines. Transfected B DNA (the most common double helical DNA structure) is sensed in the cytoplasm (cyto) by DNA receptors interferon-inducible protein 16 (IFI16) and DEAD (Asp-Glu-Ala-Asp) box polypeptide 41 (DDX41) activating the cGAMP synthase (cGAS) [98] /STING/TBK1 pathway to induce type 1 interferon production and NF-κB. An additional cytoplasmic innate immune pathway activated by transfected DNA is the cytoplasmic AIM2 inflammasome. IFI16, DDX41 and AIM2 detect DNA generically and are not sequence specific although IFI16 may preferentially recognize DNA that forms cruciforms or is negatively supercoiled [99]. By contrast, specific CpG motifs in DNA vaccines are sensed by the endosomal (endo) TLR9 innate immune receptor. To improve innate immune activation, addition of optimized immunostimulatory CpG motifs in the vector backbone may be used to increase TLR9 activation while immunostimulatory RNA expressed from the vector may be utilized to activate alterative RNA sensing innate immune receptors such as RIG-I (plasmid backbone adjuvant). Due to limited transgene expression after DNA vaccination in large animals, vector modifications and deliveries that improve transgene expression also improve adaptive immunity. Certain delivery modalities such as EP that improve gene transfer efficiency also activate innate immunity through tissue damage [100,101,102]. EP conditions need to be carefully optimized, since the optimal EP conditions for DNA vaccination are not necessarily those with the highest gene expression [103] and optimal delivery parameters vary between strains [100].
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vaccines-01-00225-f004: Molecular mechanisms of DNA vaccines. Transfected B DNA (the most common double helical DNA structure) is sensed in the cytoplasm (cyto) by DNA receptors interferon-inducible protein 16 (IFI16) and DEAD (Asp-Glu-Ala-Asp) box polypeptide 41 (DDX41) activating the cGAMP synthase (cGAS) [98] /STING/TBK1 pathway to induce type 1 interferon production and NF-κB. An additional cytoplasmic innate immune pathway activated by transfected DNA is the cytoplasmic AIM2 inflammasome. IFI16, DDX41 and AIM2 detect DNA generically and are not sequence specific although IFI16 may preferentially recognize DNA that forms cruciforms or is negatively supercoiled [99]. By contrast, specific CpG motifs in DNA vaccines are sensed by the endosomal (endo) TLR9 innate immune receptor. To improve innate immune activation, addition of optimized immunostimulatory CpG motifs in the vector backbone may be used to increase TLR9 activation while immunostimulatory RNA expressed from the vector may be utilized to activate alterative RNA sensing innate immune receptors such as RIG-I (plasmid backbone adjuvant). Due to limited transgene expression after DNA vaccination in large animals, vector modifications and deliveries that improve transgene expression also improve adaptive immunity. Certain delivery modalities such as EP that improve gene transfer efficiency also activate innate immunity through tissue damage [100,101,102]. EP conditions need to be carefully optimized, since the optimal EP conditions for DNA vaccination are not necessarily those with the highest gene expression [103] and optimal delivery parameters vary between strains [100].

Mentions: Studies using knock-out mice deficient in various innate immune receptors and signaling molecules have determined that most of the “adjuvant effect” of DNA vaccination is mediated by activation of the cytoplasmic double stranded DNA sensing stimulator of interferon genes/TANK-binding kinase 1 (STING/TBK1) dependent innate immune signaling pathway (Figure 4; reviewed in [93]). This is the primary pathway necessary to induce antigen specific B cells and CD4+ T-cells in response to DNA vaccination. However, several studies have demonstrated a role of endosomal sequence specific CpG DNA sensing Toll-like receptor 9 (TLR9) signaling in priming CD8+ T cell responses [94,95]. Cationic liposome delivered plasmid DNA clearly activates a CpG dependent inflammation response in the lung [96], so the contribution of TLR9 to DNA vaccination induced adaptive immunity may be tissue and delivery specific. Cytoplasmic DNA may also activate the absence in melanoma 2 (AIM2) inflammasome [97], but a role of inflammasome activation and the resultant caspase 1 mediated interleukin-1β production in DNA vaccine immunology has not been established.


Vector Design for Improved DNA Vaccine Efficacy, Safety and Production.

Williams JA - Vaccines (Basel) (2013)

Molecular mechanisms of DNA vaccines. Transfected B DNA (the most common double helical DNA structure) is sensed in the cytoplasm (cyto) by DNA receptors interferon-inducible protein 16 (IFI16) and DEAD (Asp-Glu-Ala-Asp) box polypeptide 41 (DDX41) activating the cGAMP synthase (cGAS) [98] /STING/TBK1 pathway to induce type 1 interferon production and NF-κB. An additional cytoplasmic innate immune pathway activated by transfected DNA is the cytoplasmic AIM2 inflammasome. IFI16, DDX41 and AIM2 detect DNA generically and are not sequence specific although IFI16 may preferentially recognize DNA that forms cruciforms or is negatively supercoiled [99]. By contrast, specific CpG motifs in DNA vaccines are sensed by the endosomal (endo) TLR9 innate immune receptor. To improve innate immune activation, addition of optimized immunostimulatory CpG motifs in the vector backbone may be used to increase TLR9 activation while immunostimulatory RNA expressed from the vector may be utilized to activate alterative RNA sensing innate immune receptors such as RIG-I (plasmid backbone adjuvant). Due to limited transgene expression after DNA vaccination in large animals, vector modifications and deliveries that improve transgene expression also improve adaptive immunity. Certain delivery modalities such as EP that improve gene transfer efficiency also activate innate immunity through tissue damage [100,101,102]. EP conditions need to be carefully optimized, since the optimal EP conditions for DNA vaccination are not necessarily those with the highest gene expression [103] and optimal delivery parameters vary between strains [100].
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4494225&req=5

vaccines-01-00225-f004: Molecular mechanisms of DNA vaccines. Transfected B DNA (the most common double helical DNA structure) is sensed in the cytoplasm (cyto) by DNA receptors interferon-inducible protein 16 (IFI16) and DEAD (Asp-Glu-Ala-Asp) box polypeptide 41 (DDX41) activating the cGAMP synthase (cGAS) [98] /STING/TBK1 pathway to induce type 1 interferon production and NF-κB. An additional cytoplasmic innate immune pathway activated by transfected DNA is the cytoplasmic AIM2 inflammasome. IFI16, DDX41 and AIM2 detect DNA generically and are not sequence specific although IFI16 may preferentially recognize DNA that forms cruciforms or is negatively supercoiled [99]. By contrast, specific CpG motifs in DNA vaccines are sensed by the endosomal (endo) TLR9 innate immune receptor. To improve innate immune activation, addition of optimized immunostimulatory CpG motifs in the vector backbone may be used to increase TLR9 activation while immunostimulatory RNA expressed from the vector may be utilized to activate alterative RNA sensing innate immune receptors such as RIG-I (plasmid backbone adjuvant). Due to limited transgene expression after DNA vaccination in large animals, vector modifications and deliveries that improve transgene expression also improve adaptive immunity. Certain delivery modalities such as EP that improve gene transfer efficiency also activate innate immunity through tissue damage [100,101,102]. EP conditions need to be carefully optimized, since the optimal EP conditions for DNA vaccination are not necessarily those with the highest gene expression [103] and optimal delivery parameters vary between strains [100].
Mentions: Studies using knock-out mice deficient in various innate immune receptors and signaling molecules have determined that most of the “adjuvant effect” of DNA vaccination is mediated by activation of the cytoplasmic double stranded DNA sensing stimulator of interferon genes/TANK-binding kinase 1 (STING/TBK1) dependent innate immune signaling pathway (Figure 4; reviewed in [93]). This is the primary pathway necessary to induce antigen specific B cells and CD4+ T-cells in response to DNA vaccination. However, several studies have demonstrated a role of endosomal sequence specific CpG DNA sensing Toll-like receptor 9 (TLR9) signaling in priming CD8+ T cell responses [94,95]. Cationic liposome delivered plasmid DNA clearly activates a CpG dependent inflammation response in the lung [96], so the contribution of TLR9 to DNA vaccination induced adaptive immunity may be tissue and delivery specific. Cytoplasmic DNA may also activate the absence in melanoma 2 (AIM2) inflammasome [97], but a role of inflammasome activation and the resultant caspase 1 mediated interleukin-1β production in DNA vaccine immunology has not been established.

Bottom Line: Innovations such as electroporation, needle free jet delivery and lipid-based carriers increase transgene expression and immunogenicity through more effective gene delivery.These next generation vectors also address potential safety issues such as antibiotic selection, and increase plasmid manufacturing quality and yield in exemplary fermentation production processes.Application of optimized constructs in combination with improved delivery platforms tangibly improves the prospect of successful application of DNA vaccination as prophylactic vaccines for diverse human infectious disease targets or as therapeutic vaccines for cancer and allergy.

View Article: PubMed Central - PubMed

Affiliation: Nature Technology Corporation/Suite 103, 4701 Innovation Drive, Lincoln, NE 68521, USA. jim@natx.com.

ABSTRACT
DNA vaccination is a disruptive technology that offers the promise of a new rapidly deployed vaccination platform to treat human and animal disease with gene-based materials. Innovations such as electroporation, needle free jet delivery and lipid-based carriers increase transgene expression and immunogenicity through more effective gene delivery. This review summarizes complementary vector design innovations that, when combined with leading delivery platforms, further enhance DNA vaccine performance. These next generation vectors also address potential safety issues such as antibiotic selection, and increase plasmid manufacturing quality and yield in exemplary fermentation production processes. Application of optimized constructs in combination with improved delivery platforms tangibly improves the prospect of successful application of DNA vaccination as prophylactic vaccines for diverse human infectious disease targets or as therapeutic vaccines for cancer and allergy.

No MeSH data available.


Related in: MedlinePlus