Combination of MIDGE-Th1 DNA vaccines with the cationic lipid SAINT-18: Studies on formulation, biodistribution and vector clearance

Endmann, Anne; Oswald, Detlef; Riede, Oliver; Talman, Eduard G.; Vos, Roelien E.; Schroff, Matthias; Kleuss, Christiane; Ruiters, Marcel H. J.; Juhls, Christiane

doi:10.1016/j.vaccine.2014.03.048

Cited by 7 publications

(11 citation statements)

References 42 publications

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“…Serum Amyloid A is known to rise 6 to 12 h after surgery or experimental inflammation and to peak after 48 or even 72 h [ 34 , 49 , 50 ]. This matches the present findings, but may also be due to prolonged response or secondary mechanisms in response to treatments with MIDGE-Th1 vectors, which are detectable long-term after application [ 51 ]. Furthermore, biopsy sampling at t24 may have contributed to the acute phase response of the horses.…”

Section: Resultssupporting

confidence: 90%

Immune response of healthy horses to DNA constructs formulated with a cationic lipid transfection reagent

Schnabel

Steinig

Koy³

et al. 2015

BMC Vet Res

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BackgroundDeoxyribonucleic acid (DNA) vaccines are used for experimental immunotherapy of equine melanoma. The injection of complexed linear DNA encoding interleukin (IL)-12/IL-18 induced partial tumour remission in a clinical study including 27 grey horses. To date, the detailed mechanism of the anti-tumour effect of this treatment is unknown.ResultsIn the present study, the clinical and cellular responses of 24 healthy horses were monitored over 72 h after simultaneous intradermal and intramuscular application of equine IL-12/IL-18 DNA (complexed with a transfection reagent) or comparative substances (transfection reagent only, nonsense DNA, nonsense DNA depleted of CG).Although the strongest effect was observed in horses treated with expressing DNA, horses in all groups treated with DNA showed systemic responses. In these horses treated with DNA, rectal temperatures were elevated after treatment and serum amyloid A increased. Total leukocyte and neutrophil counts increased, while lymphocyte numbers decreased. The secretion of tumour necrosis factor alpha (TNFα) and interferon gamma (IFNγ) from peripheral mononuclear blood cells ex vivo increased after treatments with DNA, while IL-10 secretion decreased. Horses treated with DNA had significantly higher myeloid cell numbers and chemokine (C-X-C motif) ligand (CXCL)-10 expression in skin samples at the intradermal injection sites compared to horses treated with transfection reagent only, suggesting an inflammatory response to DNA treatment.In horses treated with expressing DNA, however, local CXCL-10 expression was highest and immunohistochemistry revealed more intradermal IL-12-positive cells when compared to the other treatment groups.In contrast to non-grey horses, grey horses showed fewer effects of DNA treatments on blood lymphocyte counts, TNFα secretion and myeloid cell infiltration in the dermis.ConclusionTreatment with complexed linear DNA constructs induced an inflammatory response independent of the coding sequence and of CG motif content. Expressing IL-12/IL-18 DNA locally induces expression of the downstream mediator CXCL-10.The grey horses included appeared to display an attenuated immune response to DNA treatment, although grey horses bearing melanoma responded to this treatment with moderate tumour remission in a preceding study. Whether the different immunological reactivity compared to other horses may contributes to the melanoma susceptibility of grey horses remains to be elucidated.Electronic supplementary materialThe online version of this article (doi:10.1186/s12917-015-0452-3) contains supplementary material, which is available to authorized users.

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Section: Resultssupporting

confidence: 90%

Immune response of healthy horses to DNA constructs formulated with a cationic lipid transfection reagent

Schnabel

Steinig

Koy³

et al. 2015

BMC Vet Res

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“…Biodistribution and persistence of DNA vaccines are studied to estimate the duration of antigen expression and the risk of vector integration into host genomic DNA. 8 , 9 We examined the biodistribution of LEISHDNAVAX after a single and, in contrast to previously published results, 20 , 21 also after a series of four injections at weekly intervals. This condensed application scheme is relevant for clinical approaches with: (i) a limited number of injections over a longer period of time as accepted for prophylactic vaccinations and (ii) vaccination regimes requiring more injections in shorter intervals, for example, therapeutic vaccinations.…”

Section: Discussionmentioning

confidence: 94%

“… 16 , 17 MIDGE-Th1 vectors are MIDGE vectors with a short peptide (PKKKRKVEDPYC) covalently attached, enhancing the immune responses to encoded antigens. 18 , 19 Recently, preclinical data on biodistribution and toxicity of MIDGE and MIDGE-Th1 vectors have been published, 20 , 21 indicating an excellent safety profile after a single administration.…”

Section: Introductionmentioning

confidence: 99%

Preclinical safety and tolerability of a repeatedly administered human leishmaniasis DNA vaccine

et al. 2015

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The leishmaniases are a complex of vector-borne diseases caused by protozoan parasites of the genus Leishmania. LEISHDNAVAX is a multi-antigen, T-cell epitope-enriched DNA vaccine candidate against human leishmaniasis. The vaccine candidate has been proven immunogenic and showed prophylactic efficacy in preclinical studies. Here, we describe the safety testing of LEISHDNAVAX in naive mice and rats, complemented by the demonstration of tolerability in Leishmania-infected mice. Biodistribution and persistence were examined following single and repeated intradermal (i.d.) administration to rats. DNA vectors were distributed systemically but did not accumulate upon repeated injections. Although vector DNA was cleared from most other tissues within 60 days after the last injection, it persisted in skin at the site of injection and in draining lymph nodes. Evaluation of single-dose and repeated-dose toxicity of the vaccine candidate after i.d. administration to naive, non-infected mice did not reveal any safety concerns. LEISHDNAVAX was also well tolerated in Leishmania-infected mice. Taken together, our results substantiate a favorable safety profile of LEISHDNAVAX in both naive and infected animals and thus, support the initiation of clinical trials for both preventive and therapeutic applications of the vaccine.

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“…proteoglycans) in the extracellular matrix that may strongly interact with these complexes and hinder their mobility in the tissue. 30,31,32 Whether or not this property is desired is dependent on the context of the DNA delivery system—as it has been suggested that a depot formation may be advantageous in inducing sustained expression of antigens in non-viral DNA vaccines, 1,4,33 while others have showed that reducing the cationic surface charge can improve the distribution, and thereby promote transfection, to cells other than those found at the injection site ( i.e. , transfection of both APCs and local dermal cells).…”

Section: Discussionmentioning

confidence: 99%

Tissue-specific Calibration of Real-time PCR Facilitates Absolute Quantification of Plasmid DNA in Biodistribution Studies

White

Pouton

2016

Molecular Therapy - Nucleic Acids

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Analysis of the tissue distribution of plasmid DNA after administration of nonviral gene delivery systems is best accomplished using quantitative real-time polymerase chain reaction (qPCR), although published strategies do not allow determination of the absolute mass of plasmid delivered to different tissues. Generally, data is expressed as the mass of plasmid relative to the mass of genomic DNA (gDNA) in the sample. This strategy is adequate for comparisons of efficiency of delivery to a single site but it does not allow direct comparison of delivery to multiple tissues, as the mass of gDNA extracted per unit mass of each tissue is different. We show here that by constructing qPCR standard curves for each tissue it is possible to determine the dose of intact plasmid remaining in each tissue, which is a more useful parameter when comparing the fates of different formulations of DNA. We exemplify the use of this tissue-specific qPCR method by comparing the delivery of naked DNA, cationic DNA complexes, and neutral PEGylated DNA complexes after intramuscular injection. Generally, larger masses of intact plasmid were present 24 hours after injection of DNA complexes, and neutral complexes resulted in delivery of a larger mass of intact plasmid to the spleen.

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Combination of MIDGE-Th1 DNA vaccines with the cationic lipid SAINT-18: Studies on formulation, biodistribution and vector clearance

Cited by 7 publications

References 42 publications

Immune response of healthy horses to DNA constructs formulated with a cationic lipid transfection reagent

Immune response of healthy horses to DNA constructs formulated with a cationic lipid transfection reagent

Preclinical safety and tolerability of a repeatedly administered human leishmaniasis DNA vaccine

Tissue-specific Calibration of Real-time PCR Facilitates Absolute Quantification of Plasmid DNA in Biodistribution Studies

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