Clinical Applications of DNA Vaccines: Current Progress

Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Clinical Infectious Diseases (Impact Factor: 8.89). 08/2011; 53(3):296-302. DOI: 10.1093/cid/cir334
Source: PubMed


It was discovered almost 20 years ago that plasmid DNA, when injected into the skin or muscle of mice, could induce immune
responses to encoded antigens. Since that time, there has since been much progress in understanding the basic biology behind
this deceptively simple vaccine platform and much technological advancement to enhance immune potency. Among these advancements
are improved formulations and improved physical methods of delivery, which increase the uptake of vaccine plasmids by cells;
optimization of vaccine vectors and encoded antigens; and the development of novel formulations and adjuvants to augment and
direct the host immune response. The ability of the current, or second-generation, DNA vaccines to induce more-potent cellular
and humoral responses opens up this platform to be examined in both preventative and therapeutic arenas. This review focuses
on these advances and discusses both preventive and immunotherapeutic clinical applications.

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Available from: Bernadette Ferraro
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    • "DNA vaccines have been extensively tested in humans and have shown a good safety profile but weak immunogenicity1234. Since DNA vaccines offer a number of potential advantages over other vaccine approaches, ways to improve their immunogenicity continue to be investigated including: i) adjuvantation and/or ii) intramuscular (IM) or intradermal (ID) administration followed by in vivo electroporation (EP). "
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    ABSTRACT: Background: Strategies to enhance the immunogenicity of DNA vaccines in humans include i) co-administration of molecular adjuvants, ii) intramuscular administration followed by in vivo electroporation (IM/EP) and/or iii) boosting with a different vaccine. Combining these strategies provided protection of macaques challenged with SIV; this clinical trial was designed to mimic the vaccine regimen in the SIV study. Methods: Seventy five healthy, HIV-seronegative adults were enrolled into a phase 1, randomized, double-blind, placebo-controlled trial. Multi-antigenic HIV (HIVMAG) plasmid DNA (pDNA) vaccine alone or co-administered with pDNA encoding human Interleukin 12 (IL-12) (GENEVAX IL-12) given by IM/EP using the TriGrid Delivery System was tested in different prime-boost regimens with recombinant Ad35 HIV vaccine given IM. Results: All local reactions but one were mild or moderate. Systemic reactions and unsolicited adverse events including laboratory abnormalities did not differ between vaccine and placebo recipients. No serious adverse events (SAEs) were reported. T cell and antibody response rates after HIVMAG (x3) prime-Ad35 (x1) boost were independent of IL-12, while the magnitude of interferon gamma (IFN-γ) ELISPOT responses was highest after HIVMAG (x3) without IL-12. The quality and phenotype of T cell responses shown by intracellular cytokine staining (ICS) were similar between groups. Inhibition of HIV replication by autologous T cells was demonstrated after HIVMAG (x3) prime and was boosted after Ad35. HIV specific antibodies were detected only after Ad35 boost, although there was a priming effect with 3 doses of HIVMAG with or without IL-12. No anti-IL-12 antibodies were detected. Conclusion: The vaccines were safe, well tolerated and moderately immunogenic. Repeated administration IM/EP was well accepted. An adjuvant effect of co-administered plasmid IL-12 was not detected. Trial registration: NCT01496989.
    Full-text · Article · Aug 2015 · PLoS ONE
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    • "Numerous data show the effectiveness of experimental DNA immunizations against various viral, bacterial, parasitic and cancer diseases. However, only a few veterinary products have been registered to date in the USA and Canada, and despite several clinical trials, no human DNA vaccine is available [6] [10]. Various experimental DNA vaccines have been tested in poultry [15]. "
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    ABSTRACT: Highly pathogenic avian influenza viruses (HPAIVs) cause huge economic losses in the poultry industry because of high mortality rate in infected flocks and trade restrictions. Protective antibodies, directed mainly against hemagglutinin (HA), are the primary means of protection against influenza outbreaks. A recombinant DNA vaccine based on the sequence of H5 HA from the H5N1/A/swan/Poland/305-135V08/2006 strain of HPAIV was prepared. Sequence manipulation included deletion of the proteolytic cleavage site to improve protein stability, codon usage optimization to improve translation and stability of RNA in host cells, and cloning into a commercially available vector to enable expression in animal cells. Naked plasmid DNA was complexed with a liposomal carrier and the immunization followed the prime–boost strategy. The immunogenic potential of the DNA vaccine was first proved in broilers in near-to-field conditions resembling a commercial farm. Next, the protective activity of the vaccine was confirmed in SPF layer-type chickens. Experimental infections (challenge experiments) indicated that 100% of vaccinated chickens were protected against H5N1 of the same clade and that 70% of them were protected against H5N1 influenza virus of a different clade. Moreover, the DNA vaccine significantly limited (or even eliminated) transmission of the virus to contact control chickens. Two intramuscular doses of DNA vaccine encoding H5 HA induced a strong protective response in immunized chicken. The effective protection lasted for a minimum 8 weeks after the second dose of the vaccine and was not limited to the homologous H5N1 virus. In addition, the vaccine reduced shedding of the virus.
    Full-text · Article · Dec 2014 · Trials in Vaccinology
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    • "A promising alternative utilizes pathogen-derived subunits delivered as protein or DNA. Subunit-based vaccines show good safety, and in particular DNA vaccines are easy and fast to produce and are stable in terms of storage and temperature changes [2], [3]. Three successful DNA vaccines have been licensed for animal use [4], [5], [6], and several clinical trials with DNA vaccines have been conducted in humans [2] ( "
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    ABSTRACT: DNA vaccines based on subunits from pathogens have several advantages over other vaccine strategies. DNA vaccines can easily be modified, they show good safety profiles, are stable and inexpensive to produce, and the immune response can be focused to the antigen of interest. However, the immunogenicity of DNA vaccines which is generally quite low needs to be improved. Electroporation and co-delivery of genetically encoded immune adjuvants are two strategies aiming at increasing the efficacy of DNA vaccines. Here, we have examined whether targeting to antigen-presenting cells (APC) could increase the immune response to surface envelope glycoprotein (Env) gp120 from Human Immunodeficiency Virus type 1 (HIV-1). To target APC, we utilized a homodimeric vaccine format denoted vaccibody, which enables covalent fusion of gp120 to molecules that can target APC. Two molecules were tested for their efficiency as targeting units: the antibody-derived single chain Fragment variable (scFv) specific for the major histocompatilibility complex (MHC) class II I-E molecules, and the CC chemokine ligand 3 (CCL3). The vaccines were delivered as DNA into muscle of mice with or without electroporation. Targeting of gp120 to MHC class II molecules induced antibodies that neutralized HIV-1 and that persisted for more than a year after one single immunization with electroporation. Targeting by CCL3 significantly increased the number of HIV-1 gp120-reactive CD8+ T cells compared to non-targeted vaccines and gp120 delivered alone in the absence of electroporation. The data suggest that chemokines are promising molecular adjuvants because small amounts can attract immune cells and promote immune responses without advanced equipment such as electroporation.
    Full-text · Article · Aug 2014 · PLoS ONE
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