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HIV DNA Vaccine: Stepwise Improvements Make a Difference.

Felber BK, Valentin A, Rosati M, Bergamaschi C, Pavlakis GN - Vaccines (Basel) (2014)

Bottom Line: Inefficient DNA delivery methods and low expression of plasmid DNA have been major obstacles for the use of plasmid DNA as vaccine for HIV/AIDS.This review describes successful efforts to improve DNA vaccine methodology over the past ~30 years.DNA vaccination, either alone or in combination with other methods, has the potential to be a rapid, safe, and effective vaccine platform against AIDS.

View Article: PubMed Central - PubMed

Affiliation: Human Retrovirus Pathogenesis Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute at Frederick, P.O. Box B, Frederick, MD 21702, USA. barbara.felber@nih.gov.

ABSTRACT
Inefficient DNA delivery methods and low expression of plasmid DNA have been major obstacles for the use of plasmid DNA as vaccine for HIV/AIDS. This review describes successful efforts to improve DNA vaccine methodology over the past ~30 years. DNA vaccination, either alone or in combination with other methods, has the potential to be a rapid, safe, and effective vaccine platform against AIDS. Recent clinical trials suggest the feasibility of its translation to the clinic.

No MeSH data available.


Related in: MedlinePlus

Optimization of DNA expression and delivery: from bench to bedside. Several steps are necessary to improve the efficiency of DNA as vaccine including RNA/codon optimization of the gene, the use of optimized expression vectors, and combinations of DNA vaccine with molecular adjuvants to increase immunogenicity and using different delivery methods and sites.
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vaccines-02-00354-f001: Optimization of DNA expression and delivery: from bench to bedside. Several steps are necessary to improve the efficiency of DNA as vaccine including RNA/codon optimization of the gene, the use of optimized expression vectors, and combinations of DNA vaccine with molecular adjuvants to increase immunogenicity and using different delivery methods and sites.

Mentions: Several steps are critical to maximize the efficacy of an HIV DNA vaccine regimen (Figure 1), including optimization of plasmid DNA, optimization of immunogen, DNA delivery method, and the inclusion of molecular adjuvants. (i) To maximize antigen production from plasmid DNA, the RNA/codon optimized genes (see above) are inserted into expression vectors which typically use the human CMV enhancer/promoter and provide a potent initiation of translation signal such as the Kozak sequence (5'-gccgccaccATG(G)-3') or the HIV-1 tat sequence (5'-aagaaATG(G)-3') to initiate translation of the gene of interest and the bovine growth hormone (BGH) polyadenylation signal in a plasmid backbone optimized for replication in bacteria, which may also contain antibiotic genes as selection, typically the kanamycin gene. (ii) A second parameter to improve immunogenicity has also been extensively explored, namely the modification of the natural immunogen. One of the main features of DNA vaccines is versatility and ease of rapid alterations of the expressed immunogen. Although initially the focus was to produce authentic viral proteins as immunogens, it was discovered that modification of the produced immunogen could have advantages as a vaccine. In addition to modifications resulting in increased expression, deletions and fusions of immunogens may lead to improved secretion, rapid degradation or transport to different cellular compartments with the ultimate goal of enhancing immunogenicity. Many such variations have been applied taking advantage of the easy methodology provided by genetic engineering. For HIV/SIV antigens, several methods are employed to improve secretion using signal peptides such as tissue plasminogen activator (tPa) [45,46], or granulocyte-macrophage colony-stimulating factor (GM-CSF) [47]; addition of IgE leader to improve expression [48]; embedding the antigen within LAMP to target the fusion protein to the major histocompatibility complex type II (MHC II) processing compartment [49,50,51], fusion to MCP-3 to target immunogens to antigen-presenting cells [26,49], and fusion to signals promoting proteasomal degradation and presentation by the MHC class I molecules such as ubiquitin [52,53,54] or beta-catenin [26]. (iii) An important milestone in making DNA an attractive vaccine vehicle has been the improvement of in vivo delivery. Naked DNA is picked up poorly by primary cells and its expression is minimal. To improve delivery to the nucleus, several methods have been developed including intramuscular DNA delivery by in vivo electroporation (IM/EP) ([55,56,57,58,59,60,61] reviewed in [62,63,64,65]); skin or intradermal electroporation [66,67,68,69,70,71,72,73], skin patches [74], liposome delivery with Vaxfectin® [75,76], DNA formulated in liposomes [77]; gene gun [78] or biojector [79,80,81]. (iv) Fourth, different strategies to increase the immunogenicity of HIV DNA vaccination in macaques are being pursued, including combination of improved DNA vectors and cytokine DNAs, i.e., IL-12 [82,83,84,85,86,87,88], IL-15 [89,90,91]; IL-2 [89,92,93,94]; GM-CSF [95,96,97,98], chemokines such as RANTES [99] and costimulatory molecules such as CD40L [100,101,102]. (v) In addition to intramuscular and intradermal routes, DNA can also be delivered via the intranasal, oral, intestinal, and vaginal routes [89,92,93,103].


HIV DNA Vaccine: Stepwise Improvements Make a Difference.

Felber BK, Valentin A, Rosati M, Bergamaschi C, Pavlakis GN - Vaccines (Basel) (2014)

Optimization of DNA expression and delivery: from bench to bedside. Several steps are necessary to improve the efficiency of DNA as vaccine including RNA/codon optimization of the gene, the use of optimized expression vectors, and combinations of DNA vaccine with molecular adjuvants to increase immunogenicity and using different delivery methods and sites.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4494255&req=5

vaccines-02-00354-f001: Optimization of DNA expression and delivery: from bench to bedside. Several steps are necessary to improve the efficiency of DNA as vaccine including RNA/codon optimization of the gene, the use of optimized expression vectors, and combinations of DNA vaccine with molecular adjuvants to increase immunogenicity and using different delivery methods and sites.
Mentions: Several steps are critical to maximize the efficacy of an HIV DNA vaccine regimen (Figure 1), including optimization of plasmid DNA, optimization of immunogen, DNA delivery method, and the inclusion of molecular adjuvants. (i) To maximize antigen production from plasmid DNA, the RNA/codon optimized genes (see above) are inserted into expression vectors which typically use the human CMV enhancer/promoter and provide a potent initiation of translation signal such as the Kozak sequence (5'-gccgccaccATG(G)-3') or the HIV-1 tat sequence (5'-aagaaATG(G)-3') to initiate translation of the gene of interest and the bovine growth hormone (BGH) polyadenylation signal in a plasmid backbone optimized for replication in bacteria, which may also contain antibiotic genes as selection, typically the kanamycin gene. (ii) A second parameter to improve immunogenicity has also been extensively explored, namely the modification of the natural immunogen. One of the main features of DNA vaccines is versatility and ease of rapid alterations of the expressed immunogen. Although initially the focus was to produce authentic viral proteins as immunogens, it was discovered that modification of the produced immunogen could have advantages as a vaccine. In addition to modifications resulting in increased expression, deletions and fusions of immunogens may lead to improved secretion, rapid degradation or transport to different cellular compartments with the ultimate goal of enhancing immunogenicity. Many such variations have been applied taking advantage of the easy methodology provided by genetic engineering. For HIV/SIV antigens, several methods are employed to improve secretion using signal peptides such as tissue plasminogen activator (tPa) [45,46], or granulocyte-macrophage colony-stimulating factor (GM-CSF) [47]; addition of IgE leader to improve expression [48]; embedding the antigen within LAMP to target the fusion protein to the major histocompatibility complex type II (MHC II) processing compartment [49,50,51], fusion to MCP-3 to target immunogens to antigen-presenting cells [26,49], and fusion to signals promoting proteasomal degradation and presentation by the MHC class I molecules such as ubiquitin [52,53,54] or beta-catenin [26]. (iii) An important milestone in making DNA an attractive vaccine vehicle has been the improvement of in vivo delivery. Naked DNA is picked up poorly by primary cells and its expression is minimal. To improve delivery to the nucleus, several methods have been developed including intramuscular DNA delivery by in vivo electroporation (IM/EP) ([55,56,57,58,59,60,61] reviewed in [62,63,64,65]); skin or intradermal electroporation [66,67,68,69,70,71,72,73], skin patches [74], liposome delivery with Vaxfectin® [75,76], DNA formulated in liposomes [77]; gene gun [78] or biojector [79,80,81]. (iv) Fourth, different strategies to increase the immunogenicity of HIV DNA vaccination in macaques are being pursued, including combination of improved DNA vectors and cytokine DNAs, i.e., IL-12 [82,83,84,85,86,87,88], IL-15 [89,90,91]; IL-2 [89,92,93,94]; GM-CSF [95,96,97,98], chemokines such as RANTES [99] and costimulatory molecules such as CD40L [100,101,102]. (v) In addition to intramuscular and intradermal routes, DNA can also be delivered via the intranasal, oral, intestinal, and vaginal routes [89,92,93,103].

Bottom Line: Inefficient DNA delivery methods and low expression of plasmid DNA have been major obstacles for the use of plasmid DNA as vaccine for HIV/AIDS.This review describes successful efforts to improve DNA vaccine methodology over the past ~30 years.DNA vaccination, either alone or in combination with other methods, has the potential to be a rapid, safe, and effective vaccine platform against AIDS.

View Article: PubMed Central - PubMed

Affiliation: Human Retrovirus Pathogenesis Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute at Frederick, P.O. Box B, Frederick, MD 21702, USA. barbara.felber@nih.gov.

ABSTRACT
Inefficient DNA delivery methods and low expression of plasmid DNA have been major obstacles for the use of plasmid DNA as vaccine for HIV/AIDS. This review describes successful efforts to improve DNA vaccine methodology over the past ~30 years. DNA vaccination, either alone or in combination with other methods, has the potential to be a rapid, safe, and effective vaccine platform against AIDS. Recent clinical trials suggest the feasibility of its translation to the clinic.

No MeSH data available.


Related in: MedlinePlus