Preclinical and Clinical Safety Studies on DNA Vaccines

Schalk, J.A.C.; Mooi, Frits R.; Berbers, Guy A. M.; Aerts, Leon A G J M van; Ovelgönne, Hans; Kimman, Tjeerd G.

doi:10.4161/hv.2.2.2620

Cited by 115 publications

(70 citation statements)

References 76 publications

(120 reference statements)

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“…5,6 In addition to the differences in experimental system and to the generally immunosuppressed state of advanced cancer patients, our contrasting results may also reflect the greater difficulty in achieving robust immune responses with DNA vaccination in large animals when compared to rodents. [17][18][19] We chose to evaluate three established markers of immune activation and vaccine effectiveness, namely serum IgG levels, IFN-g production and lymphocyte proliferation. We also evaluated IL-10 production, given the evidence that this cytokine may be produced in response to Hsp65, 20 and may negatively affect immunization.…”

Section: Discussionmentioning

confidence: 99%

Immune response to vaccination with DNA-hsp65 in a phase I clinical trial with head and neck cancer patients

et al. 2009

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DNA-hsp65, a DNA vaccine encoding the 65-kDa heat-shock protein of Mycobacterium leprae (Hsp65) is capable of inducing the reduction of established tumors in mouse models. We conducted a phase I clinical trial of DNA-hsp65 in patients with advanced head and neck carcinoma. In this article, we report on the vaccine's potential to induce immune responses to Hsp65 and to its human homologue, Hsp60, in these patients. Twenty-one patients with unresectable squamous cell carcinoma of the head and neck received three doses of 150, 400 or 600 mg naked DNA-hsp65 plasmid by ultrasound-guided intratumoral injection. Vaccination did not increase levels of circulating anti-hsp65 IgG or IgM antibody, or lead to detectable Hsp65-specific cell proliferation or interferon-g (IFN-g) production by blood mononuclear cells. Frequency of antigen-induced IL-10-producing cells increased after vaccination in 4 of 13 patients analyzed. Five patients showed disease stability or regression following immunization; however, we were unable to detect significant differences between these patients and those with disease progression using these parameters. There was also no increase in antibody or IFN-g responses to human Hsp60 in these patients. Our results suggest that although DNA-hsp65 was able to induce some degree of immunostimulation with no evidence of pathological autoimmunity, we were unable to differentiate between patients with different clinical outcomes based on the parameters measured. Future studies should focus on characterizing more reliable correlations between immune response parameters and clinical outcome that may be used as predictors of vaccine success in immunosuppressed individuals.

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Section: Discussionmentioning

confidence: 99%

Immune response to vaccination with DNA-hsp65 in a phase I clinical trial with head and neck cancer patients

et al. 2009

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“…DNA vaccines have been widely used in laboratory animals to elicit comprehensive humoral and cellular immune responses. Clinical trials have shown that DNA vaccines are safe and well tolerated [15,23] . Moreover, some reports have demonstrated that DNA vaccine could produce long-lasting immunity [24][25] .…”

Section: Discussionmentioning

confidence: 99%

“…However, their use in humans is hampered by extremely high toxicity of mucosal adjuvants [12,13] . Recently, DNA vaccine without such mucosal adjuvants has been demonstrated to induce both humoral and cellular immunity and is becoming a promising treatment for viral, bacterial and parasitic pathogens [14,15] . Protective immunity against HIV, influenza virus, rabies virus, malaria and tuberculosis has been shown in animal models [16][17][18][19] .…”

Section: Introductionmentioning

confidence: 99%

Construction of recombinant attenuated Salmonella typhimurium DNA vaccine expressingH pyloriureB and IL-2

Li²,

Du³

et al. 2007

WJG

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with the sequence of mouse IL-2 in gene bank. It was confirmed by PCR and restriction enzyme digestion that H pylori ureB and mouse IL-2 genes were inserted into the eukaryotic expression vector pIRES. The experiments in vitro showed that stable recombinant live attenuated Salmonella typhimurium DNA vaccine carrying ureB and IL-2 genes was successfully constructed and the specific strips of UreB and IL-2 expressed by recombinant plasmids were detected through Western blot. Study in vivo showed that the positive rate of rapid urease test of the immunized group including ureB and ureB-IL-2 was 37.5% and 12.5% respectively, and was significantly lower than that (100%) in the control group (P < 0.01). CONCLUSION: INTRODUCTIONH pylori infection can lead to chronic gastritis, peptic ulcer disease, and is also a risk factor for g astric adenocarcinoma and mucosa-associated lymphoid tissue (MALT) lymphoma [1][2][3][4] . More than 50% of the human population worldwide are infected with H pylori. About 10%-20% of all the patients have severe diseases such as gastric or duodenal ulcer and gastric cancer. The current therapy, based on the use of proton-pump inhibitor and antibiotics [5][6][7] , is efficacious but faces potential problems like patient compliance, increasingly reported antibiotic resistance, and side effects such as abdominal pain, nausea, diarrhea [8] . METHODS: H pylori u re B a n d m o u s e I L-2 g e n e fragments were amplified by polymerase chain reaction (PCR) and cloned into pUCmT vector. DNA sequence of the amplified ureB and IL-2 genes was assayed, then cloned into the eukaryotic expression vector pIRES through enzyme digestion and ligation reactions resulting in pIRES-ureB and pIRES-ureB-IL-2. The recombinant plasmids were used to transform competent E. coli DH5α, and the positive clones were screened by PCR and restriction enzyme digestion. Then, the recombinant pIRES-ureB and pIRES-ureB-IL-2 were used to transform LB5000 and the recombinant plasmids extracted from LB5000 were finally introduced into the final host SL7207.After that, recombinant strains were grown in vitro repeatedly. In order to detect the immunogenicity of the vaccine in vitro , pIRES-ureB and pIRES-ureB-IL-2 were transfected to COS-7 cells using Lipofectamine TM 2000, the immunogenicity of expressed UreB and IL-2 proteins was assayed with SDS-PAGE and Western blot. C57BL/6 mice were orally immunized with 1 × 10 8 recombinant attenuated Salmonella typhimurium DNA vaccine. Four weeks after vaccination, mice were challenged with 1 × 10 7 CFU of live H pylori SS1. Mice were sacrificed and the stomach was isolated for examination of H pylori 4 wk post-challenge. RESULTS:The 1700 base pair ureB gene fragment amplified from the genomic DNA was consistent with the sequence of H pylori ureB by sequence analysis.The amplified 510 base pair fragment was consistent

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“…For genetic effects, the bio-distribution, persistence, and integration into the host genome were considered, which may lead to activation of oncogenes, inactivation of tumor suppressor genes, or to vertical transmission (Schalk et al, 2006). Our previous results showed that most bacteria and plasmids had cleared 8 h after oral inoculation of inhibin DNA vaccine in mice, although the plasmid may proliferate in different tissues from days 1-4.…”

Section: Requirements For An Inhibin Dna Vaccinementioning

confidence: 99%

Evaluation of attenuated Salmonella choleraesuis-mediated inhibin recombinant DNA vaccine in rats

Hui¹,

Meng²,

Guo³

et al. 2014

Genet. Mol. Res.

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ABSTRACT. DNA vaccination has been studied intensively as a potential vaccine technology. We evaluated the effect of an attenuated Salmonella choleraesuis-mediated inhibin DNA vaccine in rats. First, 15 rats were treated with different doses of an inhibin vaccine to evaluate vaccine safety. Next, 30 rats were divided into 3 groups and injected intramuscularly with the inhibin vaccine two (T1) or three times (T2) or with control bacteria (Con) at 4-week intervals. The inhibin antibody levels increased [positive/negative well (P/N) value: T1 vs Con = 2.39 ± 0.01 vs 1.08 ± 0.1; T2 vs Con = 2.36 ± 0.1 vs 1.08 ± 0.1, P < 0.05] at week 2 and were maintained at a high level in T1 and T2 until week 8, although a small decrease in T2 was observed at week 10. Rats in the T1 group showed more corpora lutea compared with the Con group (10.50 ± 0.87 vs 7.4 ± 0.51, P < 0.05). Estradiol (0.439 ± 0.052 vs 0.719 ± 0.063 ng/mL, P < 0.05) and progesterone (1.315 ± 0.2 vs 0.737 ± 0.11 ng/mL, P < 0.05) levels differed significantly at metestrus after week 10 between rats in the T1 and Con groups. However, there were no significant differences in body, ovary, uterus weights, or pathological signs in the ovaries after immunization, indicating that this vaccine is safe. In conclusion, the attenuated S. choleraesuis-mediated inhibin vaccine may be an alternative to naked inhibin plasmids for stimulating ovarian follicular development to increase the ovulation rate in rats.

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Preclinical and Clinical Safety Studies on DNA Vaccines

Cited by 115 publications

References 76 publications

Immune response to vaccination with DNA-hsp65 in a phase I clinical trial with head and neck cancer patients

Immune response to vaccination with DNA-hsp65 in a phase I clinical trial with head and neck cancer patients

Construction of recombinant attenuated Salmonella typhimurium DNA vaccine expressingH pyloriureB and IL-2

Evaluation of attenuated Salmonella choleraesuis-mediated inhibin recombinant DNA vaccine in rats

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