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Metronomic Chemotherapy Enhances Antitumor Effects of Cancer Vaccine |
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 Metronomic Chemotherapy Enhances Antitumor Effects of Cancer Vaccine by Depleting Regulatory T Lymphocytes and Inhibiting Tumor Angiogenesis.
Although cancer vaccines are emerging as innovative methods for cancer treatment, these alone have limited potential for treating measurable tumor burden. Thus, the importance of identifying anticancer strategies with greater potency is necessary. The chimeric DNA vaccine CTGF/E7 (connective tissue growth factor linked to the tumor antigen human papillomavirus 16 E7) generates potent E7-specific immunity and antitumor effects. We tested immune-modulating doses of chemotherapy in combination with the CTGF/E7 DNA vaccine to treat existing tumors in mice. Metronomic low doses of paclitaxel, not the maximal tolerable dose, are synergistic with the antigen-specific DNA vaccine. Paclitaxel, given in metronomic sequence with the CTGF/E7 DNA vaccine enhanced the vaccine's potential to delay tumor growth and decreased metastatic tumors in vivo better than the CTGF/E7 DNA vaccine alone. The two possible mechanisms of metronomic paclitaxel chemotherapy are the depletion of regulatory T cells and the inhibition of tumor angiogenesis rather than direct cancer cell cytolytic effects. Results indicate that combination treatment of metronomic chemotherapy and antigen-specific DNA vaccine can induce more potent antigen-specific immune responses and antitumor effects. This provides an immunologic basis for further testing in cancer patients.
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A DNA vaccine-encoded nucleoprotein of influenza virus fails to induce cellular immune responses in a diabetic mouse model |
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Influenza virus infections cause yearly epidemics and are a major cause of lower respiratory tract illnesses in humans worldwide. Influenza virus has long been recognized to be associated with higher morbidity and mortality in diabetic patients. Vaccination is an effective tool to prevent influenza virus infection in this group of patients. Vaccines employing recombinant-DNA technologies are an alternative to inactivated virus and live attenuated virus vaccines. Internal highly conserved viral nucleoprotein (NP) can be delivered as a DNA vaccine to provide heterosubtypic immunity, offering resistance against various influenza virus strains. In this study, we investigated the efficacy of an NP DNA vaccine for induction of cell-mediated immune responses and protection against influenza virus infection in a mouse model of diabetes. Healthy and diabetic BALB/c mice were immunized on days 0, 14, and 28 by injection of NP DNA vaccine. Two weeks after the last immunization, the cellular immune response was evaluated by gamma interferon (IFN-gamma), lymphocyte proliferation, and cytotoxicity assays. The mice were challenged with influenza virus, and the viral titers in the lungs were measured on day 4. Diabetic mice showed significantly smaller amounts of IFN-gamma production, lymphocyte proliferation, and cytotoxicity responses than nondiabetic mice. Furthermore, higher titers of the influenza virus were detected after challenge in the lungs of the diabetic mice. The present data suggest that the NP DNA vaccine with the protocol of immunization described here is not able to induce efficient cellular immune responses against influenza virus infection in diabetic mice.
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Inovio Obtains $2.8M Grant to Advance Preclinical DNA Vaccines for HCV |
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Inovio Biomedical and its collaborators from Drexel University, Cheyney University, and the University of Pennsylvania have received a $2.8 million grant to develop a DNA vaccine to treat HCV.
The money, which comes from the Pennsylvania Department of Health, will fund preclinical studies with Inovio’s vaccines. The company’s candidates are designed to treat persons who are chronically infected with HCV and have not responded to currently available therapies.
Inovio’s SynCon™ platform reportedly enables the design of universal vaccines capable of protecting against multiple strains of pathogens such as influenza, including newly emergent and unknown strains. The firm says that initial clinical data has demonstrated that its electroporation-based DNA vaccine delivery technology can safely and significantly increase gene expression and immune responses.
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MOLOGEN AG receives funding to develop a DNA vaccine against HepB |
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Berlin, GERMANY | April 6, 2010 | The Berlin based biotechnology company MOLOGEN AG has received funding for the pre-clinical development of a MIDGE®-based vaccine against hepatitis B. The project has already commenced and is being carried out jointly with Synvolux Therapeutics B. V., a company based in the Netherlands.
The project's aim is to develop a new and highly effective vaccine against infection through hepatitis B viruses. The vaccine is to be available for preventative (prophylactic) use as well as for treatment (therapeutic use). All the necessary pre-clinical studies will be carried out so that by the end of the project the vaccine will be available for testing in clinical trials.
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Priming with a DNA vaccine and boosting with an inactivated vaccine enhance the immune response |
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Priming with a DNA vaccine and boosting with an inactivated vaccine enhance the immune response against infectious bronchitis virus.
The methods of repeated immunization with inactivated vaccines have been used widely to increase antibody protection against infectious bronchitis virus (IBV). However, compared with DNA vaccines, these methods usually induce poor cellular responses. In the present study, specific pathogen-free (SPF) chickens were immunized intramuscularly with a DNA vaccine carrying the main IBV structural genes (pVAX1-S1, pVAX1-M, and pVAX1-N, respectively) and boosted with the IBV M41 strain inactivated vaccine to assess whether such a new strategy could enhance the immune responses against IBV. The protection efficacy of the DNA vaccine carrying different structural genes for priming was evaluated further. The chickens were immunized primely on day 7 and boosted 2 weeks later. After that, distribution of the DNA vaccine in vivo, the percentage of CD4+CD3+ and CD8+CD3+ subgroups of peripheral blood T-lymphocytes, and the specific IgG and virus neutralizing antibodies were measured. Chickens were then challenged by the nasal-ocular route with the IBV M41 strain 4 weeks after booster immunization. The results demonstrated that priming with a DNA vaccine encoding nucleocapsid protein (pVAX1-N) and boosting with the inactivated IBV vaccine led to the dramatic augmentation of humoral and cellular responses, and provided up to 86.7% rate of immune protection, providing an effective approach to protect chickens from IBV.
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Reports summarize DNA vaccines study results from L.R. Smith |
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Researchers detail in 'Phase 1 clinical trials of the safety and immunogenicity of adjuvanted plasmid DNA vaccines encoding influenza A virus H5 hemagglutinin,' new data in dna. "Development of vaccines against highly pathogenic avian influenza virus H5N1 subtypes posing a pandemic threat remains a priority. Limitations in manufacturing capacity and production time of conventional inactivated vaccines highlight the need for additional approaches," scientists in the United States report.
"We conducted two double-blind, placebo-controlled phase 1 studies involving a total of 103 healthy adults who received two intramuscular injections of Vaxfectin-adjuvanted plasmid DNA...
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piggyBac transposon to create HIV-1 gag transgenic insect cell lines |
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Use of the piggyBac transposon to create HIV-1 gag transgenic insect cell lines for continuous VLP production.
Insect baculovirus-produced Human immunodeficiency virus type 1 (HIV-1) Gag virus-like-particles (VLPs) stimulate good humoral and cell-mediated immune responses in animals and are thought to be suitable as a vaccine candidate. Drawbacks to this production system include contamination of VLP preparations with baculovirus and the necessity for routine maintenance of infectious baculovirus stock. We used piggyBac transposition as a novel method to create transgenic insect cell lines for continuous VLP production as an alternative to the baculovirus system. RESULTS: Transgenic cell lines maintained stable gag transgene integration and expression up to 100 cell passages, and although the level of VLPs produced was low compared to baculovirus-produced VLPs, they appeared similar in size and morphology to baculovirus-expressed VLPs. In a murine immunogenicity study, whereas baculovirus-produced VLPs elicited good CD4 immune responses in mice when used to boost a prime with a DNA vaccine, no boost response was elicited by transgenically produced VLPs. CONCLUSION: Transgenic insect cells are stable and can produce HIV Pr55 Gag VLPs for over 100 passages: this novel result may simplify strategies aimed at making protein subunit vaccines for HIV. Immunogenicity of the Gag VLPs in mice was less than that of baculovirus-produced VLPs, which may be due to lack of baculovirus glycoprotein incorporation in the transgenic cell VLPs. Improved yield and immunogenicity of transgenic cell-produced VLPs may be achieved with the addition of further genetic elements into the piggyBac integron.
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Administration of vitamin D3 improves antimetastatic efficacy of cancer vaccine therapy |
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Administration of vitamin D3 improves antimetastatic efficacy of cancer vaccine therapy of Lewis lung carcinoma.
To analyze antitumor efficacy of experimental cancer vaccine therapy combined with introduction of vitamin D3 (VD3) for treatment of Lewis lung carcinoma (3LL). Materials and Methods: Cancer vaccines composed from recombinant murine beta-defensin-2 (mBD-2) and 3LL cell lysate, or DNA, coding for mBD-2-Muc1 fusion construct cloned in pcDNA3+ vector, were prepared and used for intradermal vaccination. Experimental cancer vaccines introduced i. d. at therapeutic and prophylactic regimens to 3LLbearing C57Bl mice, were applied alone or in combination with VD3 (administered per os) and/or low-dose cyclophosphamide (CP, administered intraperitoneal). Efficacy of treatments was analyzed by primary tumor growth dynamics indexes and by metastasis rate in vaccinated animals. Results: As it has been shown, administration of the protein-based vaccine composed from mBD-2 and 3LL cell lysate in combination with VD3 and CP, but not in VD3 free setting, led to significant suppression of primary tumor growth (p < 0.005) and had significant antimetastatic effect. Introduction of VD3 with or without CP in the scheme of treatment with mBD-2-Muc1-DNA vaccine at therapeutic regimen has led to significant suppression of primary tumor (p < 0.05) and metastasis volumes (p < 0.005), while in the groups of animals treated with DNA-vaccine + VD3 with or without CP at prophylactic regimen, significant antimetastatic effect (p < 0.05) and elevation of average life-span (p < 0.05) have been registered. Conclusion: The results of this pilot study have shown promising clinical effects of VD3 administration in combination with cancer vaccinotherapy in vivo.
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gene-based vaccination against H5N1 influenza in mouse and ferret |
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Comparative efficacy of hemagglutinin, nucleoprotein, and matrix 2 protein gene-based vaccination against H5N1 influenza in mouse and ferret.
Efforts to develop a broadly protective vaccine against the highly pathogenic avian influenza A (HPAI) H5N1 virus have focused on highly conserved influenza gene products. The viral nucleoprotein (NP) and ion channel matrix protein (M2) are highly conserved among different strains and various influenza A subtypes. Here, we investigate the relative efficacy of NP and M2 compared to HA in protecting against HPAI H5N1 virus. In mice, previous studies have shown that vaccination with NP and M2 in recombinant DNA and/or adenovirus vectors or with adjuvants confers protection against lethal challenge in the absence of HA. However, we find that the protective efficacy of NP and M2 diminishes as the virulence and dose of the challenge virus are increased. To explore this question in a model relevant to human disease, ferrets were immunized with DNA/rAd5 vaccines encoding NP, M2, HA, NP+M2 or HA+NP+M2. Only HA or HA+NP+M2 vaccination conferred protection against a stringent virus challenge. Therefore, while gene-based vaccination with NP and M2 may provide moderate levels of protection against low challenge doses, it is insufficient to confer protective immunity against high challenge doses of H5N1 in ferrets. These immunogens may require combinatorial vaccination with HA, which confers protection even against very high doses of lethal viral challenge.
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Immunocontraceptive Effect of DNA Vaccine Targeting Fertilin-Beta |
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In previous study, two eukaryotic expression plasmids pSG.SS.YL and pSG.SS.C3d3.YL were successfully constructed and transfected in HEK293 cells. Now, we want to evaluate the immunocontraceptive effect of these two DNA vaccines that target the extracellular domain of sperm antigen fertilin β subunit in Kunming male mice. Method of studyq94;
DNA vaccines pSG.SS.YL and pSG.SS.C3d3.YL were injected into Kunming male mice three times at 0, 4, and 8r01;weeks, respectively. An antifertility effect was observed. Serum antibody and cytokines were also detected. Resultsq94;
Both vaccines significantly decreased both the pregnancy rate and the number of newborns. The serum levels of IL-2 and INF significantly decreased, whereas the levels of IL-4 and IL-10 significantly increased.
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GP96 C-terminal improves Her2/neu DNA vaccine. |
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DNA vaccines ensure protective immunity against tumors in a variety of experimental models. The favorite target tumor-associated antigens have been those that are frequently expressed by human tumors, such as Her2. However, the efficacy of active vaccination is limited because Her2 is a self-tolerated antigen. Many strategies have been applied to increase the efficacy of DNA vaccination, such as fusion or co-administration of Her2 with cytokine and co-stimulatory molecules. GP96 is involved in innate and adaptive immune responses and evokes potent activation and maturation of dendritic cells along with increased secretion of pro-inflammatory cytokines. On the basis of previous studies, we expected the C-terminal of GP96 to act as a package and as a suitable substitute for both cytokine and co-stimulatory genes.
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