Safety and efficacy of DNA vaccines

Stenler, Sofia; Blomberg, Pontus; Smith, C. I. Edvard

doi:10.4161/hv.28077

Cited by 50 publications

(36 citation statements)

References 20 publications

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“…In addition, the removal of all bacterial sequences from the plasmid vector, including any antibiotic resistance genes, makes mcDNA a safer alternative than plasmids. The administration of mcDNA also provided prolonged transgene expression in vivo (24), enhanced serum stability (25) and increased resistance to shearing forces (26). Since its discovery, mcDNA has been used mainly in the field of gene therapy for human use.…”

mentioning

confidence: 99%

“…Since its discovery, mcDNA has been used mainly in the field of gene therapy for human use. Most recently, the application of mcDNA as a vaccine delivery tool began in 2013 (27), and it appeared to induce a significantly stronger immune response than the parental plasmids (25,28), especially in terms of the CD8 ϩ T cell-mediated cellular immune response (27). However, the application of mcDNA in vaccine studies has mainly focused on human diseases, such as cancer (29)(30)(31) and hepatitis B virus (HBV) (32) and HIV (33) infections, probably due to the complicated purification process, low production rate, and high preparation cost of mcDNA, which dramatically restrict the application of this system in practical veterinary applications.…”

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confidence: 99%

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A Novel Cre Recombinase-Mediated In Vivo Minicircle DNA (CRIM) Vaccine Provides Partial Protection against Newcastle Disease Virus

Jiang

Gao

et al. 2019

Appl Environ Microbiol

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Minicircle DNA (mcDNA), which contains only the necessary components for eukaryotic expression and is thus smaller than traditional plasmids, has been designed for application in genetic manipulation. In this study, we constructed a novel plasmid containing both the Cre recombinase under the phosphoglycerate kinase (PGK) promoter and recombinant lox66 and lox71 sites located outside the cytomegalovirus (CMV) expression cassette. The strictly controlled synthesis of Cre recombinase in vivo maintained the complete form of the plasmid in vitro, whereas the in vivo production of Cre transformed the parental plasmid to mcDNA after transfection. The newly designed Cre recombinase-mediated in vivo mcDNA platform, named CRIM, significantly increased the nuclear entry of mcDNA, followed by increased production of mRNA and protein, using enhanced green fluorescent protein (EGFP) as a model. Similar results were also observed in chickens when the vaccine was delivered by the regulated-delayed-lysis Salmonella strain 11218, where significantly increased production of EGFP was observed in chicken livers. Then, we used the HN gene of genotype VII Newcastle disease virus as an antigen model to construct the traditional plasmid pYL43 and the novel mcDNA plasmid pYL47. After immunization, our CRIM vaccine provided significantly increased protection against challenge compared with that of the traditional plasmid, providing us with a novel mcDNA vaccine platform. IMPORTANCE Minicircle DNA (mcDNA) has been considered an attractive alternative to DNA vaccines; however, the relatively high cost and complicated process of purifying mcDNA dramatically restricts the application of mcDNA in the veterinary field. We designed a novel in vivo mcDNA platform in which the complete plasmid could spontaneously transform into mcDNA in vivo. In combination with the regulateddelayed-lysis Salmonella strain, the newly designed mcDNA vaccine provides us with an elegant platform for veterinary vaccine development.

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confidence: 99%

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confidence: 99%

A Novel Cre Recombinase-Mediated In Vivo Minicircle DNA (CRIM) Vaccine Provides Partial Protection against Newcastle Disease Virus

Jiang

Gao

et al. 2019

Appl Environ Microbiol

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“…Alveolar infiltrates were not observed in the lungs of mice treated with Dg-cSCK:pDNA nanocomplexes. While Dg-cSCK has the capacity for successful in vivo gene delivery, it is also possible that Dg-cSCK carriage of new generation minicircle DNA plasmids lacking prokaryotic sequences or plasmids with eukaryotic promoters would enhance both levels and maintenance of gene expression[59, 60]. Due to its relative biocompatibility, gene transfer potential, and degradability, therapeutic plasmids such as those for modulating infection, inflammation or fibrosis could be delivered in an identical manner as pLuc in this study to provide therapy for acute (e.g., respiratory virus infection) and chronic (e.g., pulmonary fibrosis) lung diseases with minimal adverse effects from the nanocarrier[10, 11].…”

Section: Resultsmentioning

confidence: 99%

In vivo fate tracking of degradable nanoparticles for lung gene transfer using PET and Ĉerenkov imaging

et al. 2016

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Nanoparticles (NPs) play expanding roles in biomedical applications including imaging and therapy, however, their long-term fate and clearance profiles have yet to be fully characterized in vivo. NP delivery via the airway is particularly challenging, as the clearance may be inefficient and lung immune responses complex. Thus, specific material design is required for cargo delivery and quantitative, noninvasive methods are needed to characterize NP pharmacokinetics. Here, biocompatible poly(acrylamidoethylamine)-b-poly(DL-lactide) block copolymer-based degradable, cationic, shell-cross-linked knedel-like NPs (Dg-cSCKs) were employed to transfect plasmid DNA. Radioactive and optical beacons were attached to monitor biodistribution and imaging. The preferential release of cargo in acidic conditions provided enhanced transfection efficiency compared to non-degradable counterparts. In vivo gene transfer to the lung was correlated with NP pharmacokinetics by radiolabeling Dg-cSCKs and performing quantitative biodistribution with parallel positron emission tomography and Čerenkov imaging. Quantitation of imaging over 14 days corresponded with the pharmacokinetics of NP movement from the lung to gastrointestinal and renal routes, consistent with predicted degradation and excretion. This ability to noninvasively and accurately track NP fate highlights the advantage of incorporating multifunctionality into particle design.

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“…Although integration and possible insertional mutagenesis also are safety concerns with many gene vectors, particularly viruses, even with very effective delivery methods (e.g., electroporation), the in vivo integration rates of nonviral vectors (plasmids and MCs) are approximately three orders of magnitude below the rate of spontaneous gene-inactivating mutations (35)(36)(37)(38)(39). MCs also are more resistant than plasmids to shearing stress and linearization (40,41), an important characteristic that has been correlated with integration rates (42). Therefore, although extensive safety testing must be done before eventual clinical translation, our tumoractivatable MC system should be considered relatively safe.…”

Section: Discussionmentioning

confidence: 99%

Detecting cancers through tumor-activatable minicircles that lead to a detectable blood biomarker

Ronald

Chuang

Dragulescu-Andrasi

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Earlier detection of cancers can dramatically improve the efficacy of available treatment strategies. However, despite decades of effort on blood-based biomarker cancer detection, many promising endogenous biomarkers have failed clinically because of intractable problems such as highly variable background expression from nonmalignant tissues and tumor heterogeneity. In this work we present a tumor-detection strategy based on systemic administration of tumor-activatable minicircles that use the pan-tumorspecific Survivin promoter to drive expression of a secretable reporter that is detectable in the blood nearly exclusively in tumor-bearing subjects. After systemic administration we demonstrate a robust ability to differentiate mice bearing human melanoma metastases from tumor-free subjects for up to 2 wk simply by measuring blood reporter levels. Cumulative change in reporter levels also identified tumor-bearing subjects, and a receiver operator-characteristic curve analysis highlighted this test's performance with an area of 0.918 ± 0.084. Lung tumor burden additionally correlated (r 2 = 0.714; P < 0.05) with cumulative reporter levels, indicating that determination of disease extent was possible. Continued development of our system could improve tumor detectability dramatically because of the temporally controlled, high reporter expression in tumors and nearly zero background from healthy tissues. Our strategy's highly modular nature also allows it to be iteratively optimized over time to improve the test's sensitivity and specificity. We envision this system could be used first in patients at high risk for tumor recurrence, followed by screening high-risk populations before tumor diagnosis, and, if proven safe and effective, eventually may have potential as a powerful cancer-screening tool for the general population.cancer | minicircles | tumor-specific promoter | reporter gene | blood test

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Safety and efficacy of DNA vaccines

Cited by 50 publications

References 20 publications

A Novel Cre Recombinase-Mediated In Vivo Minicircle DNA (CRIM) Vaccine Provides Partial Protection against Newcastle Disease Virus

A Novel Cre Recombinase-Mediated In Vivo Minicircle DNA (CRIM) Vaccine Provides Partial Protection against Newcastle Disease Virus

In vivo fate tracking of degradable nanoparticles for lung gene transfer using PET and Ĉerenkov imaging

Detecting cancers through tumor-activatable minicircles that lead to a detectable blood biomarker

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