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At least 19 recordsLinked to original sources

PubMed2001

Protection against Leishmania donovani infection by DNA vaccination: increased DNA vaccination efficiency through inhibiting the cellular p53 response.

DNA-vaccination holds great promise for the future of vaccine development against infectious diseases, especially in developing countries. We therefore investigated the possibility of using DNA-vaccination against Leishmania donovani infection with the A2 virulence gene and whether inhibiting the cellular p53 response could increase the effectiveness of the A2 DNA vaccine. p53, also known as the guardian of the genome, is activated following DNA transfection and has pleotropic effects on cells, which could have adverse effects on the effectiveness of DNA-vaccination. Two major observations are reported within. First, vaccination with the A2 gene induced both humoral and cellular immune responses against A2 which provided significant protection against infection with L. donovani. Second, inhibition of p53 with human papillomavirus E6 resulted in higher expression of heterologous transfected genes in vitro and more efficient DNA-vaccination in vivo. These results have important implications for DNA vaccination against leishmaniasis and potentially against other infectious diseases.

Animals↗

PubMed2004

The hybrid cytomegalovirus enhancer/chicken beta-actin promoter along with woodchuck hepatitis virus posttranscriptional regulatory element enhances the protective efficacy of DNA vaccines.

DNA vaccines represent a novel and powerful alternative to conventional vaccine approaches. They are extremely stable and can be produced en masse at low cost; more importantly, DNA vaccines against emerging pathogens or bioterrorism threats can be quickly constructed based solely upon the pathogen's genetic code. The main drawback of DNA vaccines is that they often induce lower immune responses than traditional vaccines, particularly in nonrodent species. Thus, improving the efficacy of DNA vaccines is a critical issue in vaccine development. In this study we have enhanced the efficacy of DNA vaccines by adopting strategies that increase gene expression. We generated influenza-hemagglutinin (HA)-encoding DNA vaccines that contain the hybrid CMV enhancer/chicken beta-actin (CAG) promoter and/or the mRNA-stabilizing post-transcriptional regulatory element from the woodchuck hepatitis virus (WPRE). Mice were immunized with these DNA vaccines, and the influenza-HA-specific cellular and humoral immune responses were compared with a conventional, HA-encoding DNA vaccine whose gene expression was driven by the CMV immediate-early promoter (pCMV-HA). CAG promoter-driven DNA vaccines elicited significantly higher humoral and cellular immune responses compared with the pCMV-HA vaccine. DNA vaccines consisting of both CAG and WPRE elements (pCAG-HA-WPRE) induced the highest level of protective immunity, such that immunization with 10-fold lower DNA doses prevented death in 100% of the mice upon lethal viral challenge, whereas all mice immunized with the conventional pCMV-HA vaccine succumbed to influenza infection.

Actins↗

PubMed2006

Preclinical and clinical safety studies on DNA vaccines.

DNA vaccines are based on the transfer of genetic material, encoding an antigen, to the cells of the vaccine recipient. Despite high expectations of DNA vaccines as a result of promising preclinical data their clinical utility remains unproven. However, much data is gathered in preclinical and clinical studies about the safety of DNA vaccines. Here we review current knowledge about the safety of DNA vaccines. Safety concerns of DNA vaccines relate to genetic, immunologic, toxic, and environmental effects. In this review we provide an overview of findings related to the safety of DNA vaccines, obtained so far. We conclude that the potential risks of DNA vaccines are minimal. However, their safety issues may differ case-by-case, and they should be treated accordingly.

Animals↗

PubMed2004

Approaches to enhance the efficacy of DNA vaccines.

DNA vaccines consist of antigen-encoding bacterial plasmids that are capable of inducing antigen-specific immune responses upon inoculation into a host. This method of immunization is advantageous in terms of simplicity, adaptability, and cost of vaccine production. However, the entry of DNA vaccines and expression of antigen are subjected to physical and biochemical barriers imposed by the host. In small animals such as mice, the host-imposed impediments have not prevented DNA vaccines from inducing long-lasting, protective humoral, and cellular immune responses. In contrast, these barriers appear to be more difficult to overcome in large animals and humans. The focus of this article is to summarize the limitations of DNA vaccines and to provide a comprehensive review on the different strategies developed to enhance the efficacy of DNA vaccines. Several of these strategies, such as altering codon bias of the encoded gene, changing the cellular localization of the expressed antigen, and optimizing delivery and formulation of the plasmid, have led to improvements in DNA vaccine efficacy in large animals. However, solutions for increasing the amount of plasmid that eventually enters the nucleus and is available for transcription of the transgene still need to be found. The overall conclusions from these studies suggest that, provided these critical improvements are made, DNA vaccines may find important clinical and practical applications in the field of vaccination.

Animals↗

PubMed2004

Cytotoxic T-lymphocyte-, and helper T-lymphocyte-oriented DNA vaccination.

DNA vaccines have advantages over other types of vaccines in that they can induce strong cellular immune responses, namely cytotoxic T lymphocytes (CTL) and helper T lymphocytes (Th). DNA vaccines are therefore considered a promising alternative to attenuated live vaccines in the field of infectious diseases. So far, various DNA vaccines have been generated and tried to induce a particular cellular immune response by virtue of recombinant DNA technology. DNA vaccines have been designed for efficient transcription and translation of target genes by a variety of strategies. Also, various DNA vaccine strategies for induction of specific CTL and Th have been reported by taking into consideration antigen presentation pathways and the strategies have been shown to be effective to elicit particular T-cell responses. In this paper, we have reviewed these strategies, including our study on epitope-specific T-cell induction by DNA vaccination against Listeria monocytogenes infection. From this review, it has been surmised that, to induce strong immune responses by DNA vaccines, the immunization route and the immunization regimen, such as heterologous "prime-boost" regimen, should also be considered.

Animals↗

PubMed2003

Adjuvant formulations and delivery systems for DNA vaccines.

DNA vaccines have become a reliable and major means to elicit immune responses in the past decade. We and others have attempted to obtain stronger, more long lasting, and optimized immune responses, subsequent to the pioneering works demonstrating the ability of plasmid DNA to raise specific immune responses. Advances in molecular biology and biotechnology allow the application of various adjuvants, immunologic agents that increase the antigenic response, in DNA vaccines. Adjuvants can be broadly separated into two classes based on their origin-genetic and conventional. Genetic adjuvants are expression vectors of cytokines or other molecules that can modulate immune responses when administered with a vaccine antigen. Conventional adjuvants are chemical compounds that enhance, prolong, or modulate antigen-specific immune responses. The use of an appropriate adjuvant is pivotal in optimizing the response to DNA vaccines. Moreover, DNA vaccines themselves possess their own adjuvant activity because of the presence of unmethylated CpG motifs in particular base contents. The route of inoculation is also a critical factor in determining the outcome of vaccination. It is well known that intramuscular injection preferentially induces Th1-type immunity, whereas particle bombardment by gene gun predominantly induces Th2-type response. This article focuses on providing the detailed procedure to construct genetic adjuvant plasmids and prepare DNA vaccines formulated with conventional adjuvants. We also offer a practical guide for the procedure of intramuscular DNA injection.

Adjuvants, Immunologic↗

PubMed2000

DNA vaccines.

DNA vaccination or genetic immunization is a rapidly developing technology that offers new approaches for the prevention and therapy of disease. Regarding the inoculation method of DNA vaccine, we recommend the gene gun delivery system, which is a highly reliable method compared to intramuscular inoculation. DNA vaccines could have potential advantages over other types of vaccines in that these vaccines can induce strong cellular immune responses, cytotoxic T lymphocytes and type 1 helper T cells, without resorting to live organisms or complicated protein formulation. The cellular immune responses are especially required for the protection against infections with intracellular pathogens such as viruses and Mycobacterium tuberculosis and protection against cancers, suggesting that they seem to be suitable targets of DNA vaccines. We describe here that their application to bacterial infections requires optimization of codon usage in the DNA vaccines to the host animal to improve translational efficiencies of the bacteria genes. DNA vaccines for a variety of pathogens and cancers have now entered phase I/II human clinical trials.

Animals↗

PubMed2005

A DNA vaccine coding for gB and gD of pseudorabies virus (suid herpes type 1) primes the immune system in the presence of maternal immunity more efficiently than conventional vaccines.

DNA vaccines are capable of priming the immune system of neonates in the presence of maternal antibodies. However, it is still not clear whether the extent of priming and protection against challenge infections induced by a DNA vaccine in maternally immune newborns is better than that induced by conventional vaccines. To study this, we used the pseudorabies virus (PRV) infection model in the natural host, the pig. We compared the efficacy of a DNA vaccine with the efficacy of a conventional modified live vaccine (MLV) and an inactivated vaccine (IV) in maternally immune newborn piglets. We measured the priming of the immune response and the degree of protection against challenge infection for all vaccine types. We vaccinated piglets with or without maternal immunity twice, at the age of 5 and 9 weeks, and we assessed protection by challenge infection with virulent PRV at the age of 15 weeks. Vaccination with DNA or conventional vaccines induced both humoral and cell-mediated immune responses in maternally immune animals. DNA vaccination seemed not to suffer from suppression by maternal immunity and resulted in similar or stronger immune responses in maternally immune piglets as compared in naïve piglets. In contrast, vaccination with conventional vaccines resulted in weaker immune responses in maternally immune piglets than in naïve piglets. Moreover, DNA vaccination provided better protection against challenge infection in maternally immune piglets than in naive piglets, whereas vaccination with conventional vaccines did not.

Animals↗

PubMed2006

A truncated C-terminal fragment of Mycobacterium tuberculosis HSP70 gene enhanced potency of HBV DNA vaccine.

DNA vaccine represents an attractive approach to therapy of chronic hepatitis B virus (HBV) infection because of its ability to generate antigen-specific immunity; nevertheless, there is still a need to increase the potency of DNA vaccine. Mycobacterium tuberculosis heat shock protein70 (HSP70) has both chaperon and cytokine functions, and has been shown to act as an adjuvant when co-administered with peptide antigens or given as fusion proteins. Here we evaluated the effects of two truncated HSP70 molecules, N-terminal domain (HSP70(1-360), amino acids 1-360) and C-terminal domain (HSP70(359-610), amino acids 359-610) of mycobacterial HSP70, on the potency of antigen-specific immunity generated by a HBV DNA vaccination. We found that only the HSP70(359-610)-fused HBV DNA vaccination resulted in a significant increase in hepatitis B surface antigen (HBsAg)-specific humoral response, while the HSP70(1-360)- or the complete HSP70 molecule-fused vaccine did not. Moreover, HSP70(359-610)-fused DNA vaccine did not induce anti-HSP70 antibody. Interestingly, HSP70(359-610) not only enhanced HBsAg-specific cytotoxic lymphocytes (CTL) responses but also overcame the epitope suppression caused by L(d)-restricted epitope. Meanwhile, HSP70(369-610) mediated T helper (Th) cell balance towards Th1 pathway. In a HBV transgenic mouse model, the HSP70(359-610) fusion vaccine facilitated clearance of circulating HBsAg and down-regulation of HBV replication. These results suggested that the truncated mycobacterial HSP70 molecule, HSP70(359-610), might be a superior candidate to deliver the adjuvant function in HBV DNA vaccination instead of the complete HSP70 molecule.

Adjuvants, Immunologic↗

PubMed2003

Technical and regulatory hurdles for DNA vaccines.

DNA vaccines have been widely used in laboratory animals and non-human primates over the last decade to induce antibody and cellular immune responses. This approach has shown some promise, in models of infectious diseases of both bacterial and viral origin as well as in tumour models. Clinical trials have shown that DNA vaccines appear safe and well tolerated, but need to be made much more potent to be candidates for preventive immunisation of humans. This review describes recent work to improve the delivery of plasmid DNA vaccines and also to increase the immunogenicity of antigens expressed from the DNA vaccine plasmids, including various formulations and molecular adjuvants. Because DNA vaccines are relatively new and represent a novel vaccine technology, certain safety issues, such as the potential for induction of autoimmune disease and integration into the host genome, must be examined carefully. If potency can be improved and safety established, plasmid DNA vaccines offer advantages in speed, simplicity, and breadth of immune response that may be useful for the immunisation of humans against infectious diseases and cancers.

Adjuvants, Immunologic↗

PubMed2002

Different profile of CD8+ effector T cells induced in Der p 1-allergic and naïve mice by DNA vaccination.

DNA vaccination holds great promise in both prophylactic and therapeutic vaccines. Recent evidence suggests that DNA vaccines could be powerful therapies countering Th2-mediated disorders such as allergies. Here, we studied the allergen-specific CD4+ and CD8+ T cell populations induced following immunization of allergic and non-allergic mice with DNA vaccine vectors encoding discrete epitopes of the house dust mite (HDM) Dermatophagoides pteronyssinus group I (Der p 1) allergen. Specifically, mice were sensitized to Der p 1 and exhibited a strong Th2/allergic response. Sensitized and non-allergic mice were then compared for their responses to DNA immunization. Using Elispot analysis, we demonstrate that allergic/vaccinated mice generate a mixed Th1/Th2 response against the allergen with high numbers of allergen-specific CD4+ T cells secreting IFN-gamma or IL-4, whereas in non-allergic/vaccinated mice a polarized Th1 response was dominant. Allergen-specific CD8+ T cells secreting IFN-gamma were induced at equal frequencies in both allergic and non-allergic mice. However, the CD8+ T cells from allergic mice were markedly deficient in their cytotoxic potential when compared to their counterparts in non-allergic mice. These results indicate that during an ongoing Th2 response, DNA vaccination leads to the generation of a distinct population of non-cytotoxic/regulatory CD8+ T cells.

Allergens↗

PubMed2000

Relative potency of cellular and humoral immune responses induced by DNA vaccination.

DNA vaccines can prime broad-based immune responses in small animal models. In the present study, we sought to evaluate the relative ability of DNA vaccines to induce humoral and cellular immune responses. Using a DNA vaccine encoding HIV gag in mice, we observed that CD8+ T cell responses were primed more readily than were antibody responses, particularly at low doses of DNA. These CD8+ T cell responses were detected in spleen cells, as well as at local sites such as the lung and draining lymph nodes. The potency of the HIV gag DNA vaccine used was sufficient to prime strong CTL responses in macaques, but only low to undetectable antibody responses. Therefore, DNA vaccines appear able to prime strong, broad CTL but only modest antibody responses. These results may have implications on the development of vaccines against infectious diseases where both CTL and antibody responses are desired, such as HIV.

AIDS Vaccines↗

PubMed2001

Tuberculosis DNA vaccines.

DNA vaccines have been the subject of intense investigation for the past 10 y, during which time several tuberculosis (TB) DNA vaccines have been shown to confer protective immunity in animal models. So far, proof of principle for priming of immune responses by a naked DNA vaccine (malaria) has been demonstrated in humans, but potency remains a significant limitation. However, new DNA vaccine formulations and delivery systems are being developed with markedly improved potency in animal models. Therefore, there is a clear path to the human clinical testing of TB DNA vaccines.

Animals↗

PubMed2006

Induction of protective and therapeutic antitumour immunity using a novel tumour-associated antigen-specific DNA vaccine.

DNA vaccination has become an attractive immunization strategy against cancer. However, a major problem of DNA vaccination is its limited potency to be taken up by the antigen-presenting cells. In contrast, loss of immunogenic epitopes of tumour cells has urged the development of vaccines against multiple epitopes. In this study, we developed a novel strategy for the APC to efficiently cross-present a fusion tumour antigen, which contains both MHC class I-restricted and class II-restricted T-cell epitopes from Her-2/neu and p53 in a cognate manner. The N-terminus of the fusion Her-2/neu, p53 protein was linked to the sequence encoding for human secondary lymphoid-tissue chemokine for secretion and chemokinesis, and the C-terminus of the fusion protein was linked to a cell-binding domain of IgG (Fc portion, the cell-binding domain of IgG) for receptor-mediated internalization. Here, we show that the introduction of fused-gene DNA vaccine by gene gun reduced the size of established tumours and prolonged the lifespan of tumour-bearing mice. Results show that this DNA vaccination strategy can broadly enhance the antigen-specific cellular and humoral immune responses. This vaccine is capable of inducing adaptive immunity and may provide a novel, generic design for the development of therapeutic and preventive DNA vaccines.

Animals↗

PubMed2003

Accelerated immune response to DNA vaccines.

DNA vaccines offer considerable promise for improvement over conventional vaccines. For the crucial step of delivering DNA vaccines intracellularly, electroporation (EP) has proven to be highly effective. This method has yielded powerful humoral and cellular responses in various species, including nonhuman primates. In an attempt to further improve DNA vaccination we used micron-size gold particles (which do not bind or adsorb DNA) as a particulate adjuvant which was coinjected with DNA intramuscularly into mice, followed by EP of the target site. The presence of gold particles accelerated the antibody response significantly. Maximum titers against hepatitis B surface antigen (HBsAg) were reached after one boost in 6 weeks, whereas 8 weeks were required without particles. These immunizations were effective in protecting mice against tumor challenge with cancer cells expressing HBsAg as a surrogate cancer antigen. Computer modeling of electric fields and gene expression studies indicate that gold particles do not stimulate EP and subsequent antigen expression. The particles may act as an attractant for immune cells, especially antigen presenting cells. We conclude that particulate adjuvants combined with DNA vaccine delivery by EP reduces the immune response time and may increase vaccine efficacy. This method may become valuable for developing prophylactic as well as therapeutic vaccines. The rapid response may be of particular interest in countering bio-terrorism.

Adenocarcinoma↗

PubMed1996

Toward the development of DNA vaccines.

DNA vaccination has proved to be a generally applicable technology in various preclinical animal models of infectious and noninfectious disease and several DNA vaccines have now entered phase I human clinical trials. It is too early to predict the effectiveness of DNA vaccines in humans and whether improved formulations of DNA vaccines will be required but several lines of investigation have suggested ways in which DNA vaccines may be improved, such as increases in expression, facilitation of DNA targeting or uptake, and enhancement of immune responses.

Animals↗

PubMed2003

[DNA vaccines].

DNA vaccination is a new vaccine approach used to induce an immune response to an antigen protein expressed in vivo. It is based on the introduction, via intramuscular injections, particle bombardment, or nasal spray, of a purified DNA plasmid encoding for the polypeptide sequence. The resulting in situ protein synthesis involves biosynthetic processing and post-translational modifications. The effectiveness of DNA vaccines has been demonstrated in many animal models. Cell-mediated immunity (Th1 and Th2 responses) and humoral immunity can be obtained. B-cell production of antibodies is generally weaker than induced by traditional vaccines. Various approaches to boost the immune response have been studied, including co-administration of cytokines, co-stimulation with specific genes, and addition of targeting molecules. Research with animal models has shown that DNA vaccines are safe. Deleterious immune responses, such as autoimmunity and development of tolerance in response to persistent expression of a foreign antigen, have not been observed. Phase I and Phase II clinical trials with DNA vaccines have been conducted for HIV, HBV, HVC, HSV, tuberculosis, and malaria. Clinical trials are also in hand for cancer and the treatment of allergies. This new approach of DNA vaccination offers new hope because of their low cost and manufacturing stability at ambient temperature.

Animals↗

PubMed2003

Microparticles and nanoparticles as delivery systems for DNA vaccines.

DNA vaccines, also referred to as genetic vaccines, are generating significant preclinical and clinical interest. It has been proven that the expression of an antigen or antigens from plasmid DNA (pDNA) may elicit both humoral and cellular immune responses. Therefore, DNA vaccines may have potential as new vaccines for important pathogens such as HIV, hepatitis C, tuberculosis, and malaria. However, the clinical results using "naked" pDNA have been disappointing in the breadth and depth of the immune response and the relatively high doses of pDNA needed to elicit a response. Clinical trials with the gene gun have been promising, but it is unclear whether this technology will be commercially viable. As a result, there exists a clear need for new vaccine delivery systems that can be administered at low doses to elicit strong humoral and cellular immune responses. One promising approach is the development of microparticles and nanoparticles as delivery systems for DNA vaccines. In this review, the application of microparticles and nanoparticles as DNA vaccine delivery systems will be critically reviewed with a primary focus on those systems that have generated in vivo immune responses.

Adjuvants, Immunologic↗