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DNA Vaccine
DNA vaccines are the newest type of vaccine and consist of only a DNA molecule encoding the antigen(s) of interest and, possibly, costimulatory molecules such as cytokines.

From: Principles of Molecular Virology (Sixth Edition), 2016

Related terms:
AntigenObstetric DeliveryProteinVaccineInfectionImmune ResponseGeneDNAPlasmidVaccination
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DNA Vaccines
John J. Donnelly, Margaret A. Liu, in Encyclopedia of Immunology (Second Edition), 1998

DNA vaccines encoding proteins of M. tuberculosis have been shown to be effective for generating the desired cellular responses and protection from challenge. This model has been instructive, in that in this system the mycobacterial protein is made by the mammalian host cell rather than by the organism, and therefore the post-translational modifications of the protein have in some cases been different from those of the native protein. To avoid the glycosylation that was seen of one particular antigen, antigen 85C, selected point mutations were introduced to remove the N-linked glycosylation sites and thus to generate an antigen more like the native protein in its lack of glycosylation.

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DNA vaccines and their application against parasites – promise, limitations and potential solutions
Peter M. Smooker, … Terry W. Spithill, in Biotechnology Annual Review, 2004

3.5. Future of DNA vaccination against intracellular parasites
DNA vaccines, when used in their present form against protozoans, particularly in non-rodent host models, are not effective at preventing disease. However, effectively “priming” the immune system using DNA vaccines is an immediate practical application. Studies from malaria in particular, as described above, have shown that DNA vaccines in their present forms are not adequate to prevent disease. Boosting the immune system after the DNA immunizing antigen has been used to prime the immune system is the most practical outcome of DNA vaccines in their present forms. The enhancement of antigen recognition and augmentation of the immune system against invading parasites by DNA vaccination are now discussed further.

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DNA Vaccines for the Induction of Immune Responses in Mucosal Tissues
Milan Raska, Jaroslav Turanek, in Mucosal Immunology (Fourth Edition), 2015

DNA vaccines represent an innovative approach allowing the induction of humoral and cell-mediated antigen-specific immune response in systemic and mucosal compartments. Vaccines consist of plasmid DNA-encoding antigens that become expressed in host cells, including species-specific posttranslational modifications. DNA vaccines elicit CD8 T cell responses in most experiments through cross-presentation of antigen. Because most pathogens invade hosts through mucosal surfaces, the induction of mucosal and systemic immunity is of paramount importance. Although systemic DNA vaccination exhibits high efficiency, generally weaker immune responses are induced by mucosal DNA administration. However, systemic immunization with selected viral and bacterial vaccines may also protect against mucosal infections. Furthermore, in contrast to high immunogenicity confirmed in small experimental animals, human DNA vaccines require further optimization to exhibit a protective effect. Therefore, various systems for the delivery of DNA vaccines and various immunomodulatory molecules coadministered with DNA vaccines have been developed to optimize the immune response and protection.

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Next Generation of Rabies Vaccines
Zhi Quan Xiang, Hildegund C.J. Ertl, in Rabies (Third Edition), 2013

6.4 DNA Vaccines
DNA vaccines are very easy to construct, and they are well-tolerated in humans. Numerous studies with DNA vaccine to rabies virus reported induction of protective VNA titers using various routes of immunization in experimental animals, ranging from mice, cats and dogs, to monkeys (Bahloul et al., 2003; Bahloul et al., 2006; Lodmell, Ewalt, Parnell, Rupprecht, & Hanlon, 2006; Lodmell, Parnell, Bailey, Ewalt, & Hanlon, 2002; Lodmell, Parnell, Weyhrich, & Ewalt, 2003; Tesoro Cruz et al., 2008; Tesoro Cruz, Hernandez Gonzalez, Alonso Morales, & Aguilar-Setien, 2006; Xiang, Spitalnik et al., 1995). Some studies reported protection with DNA vaccines given to already infected animals (Bahloul et al., 2003; Lodmell et al., 2002; Tesoro Cruz et al., 2008). Unfortunately, in humans, DNA vaccines were found to be poorly immunogenic. Addition of genetic adjuvants (Xiang & Ertl, 1995), prime boost regimens in which DNA vaccines are typically used for priming followed by a booster immunization with a recombinant viral vector (Lodmell & Ewalt, 2000) or novel delivery methods such a injection of DNA followed by electroporation (Sardesai & Weiner, 2011), increase the immunogenicity of DNA vaccine in animals and for some antigens in humans as well. To what degree such modifications affect the vaccine’s safety remains to be investigated in more depth. Prime-boost regimens, although highly effective, may not be suited for PEP, and their cost-effectiveness for preventive vaccination is unlikely. The suitability of electroporation, which increases immune responses by enhancing transduction rates, for immunization in developing countries remains to be explored.

Efficacy was also reported for Sindbis virus-based DNA vaccines (Saxena et al., 2008), which, unlike conventional DNA vaccine, generate self-replicate RNA transcripts and thus achieve superior protein-expression levels.

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The Flaviviruses: Detection, Diagnosis, and Vaccine Development
Robert Putnak, … Connie Schmaljohn, in Advances in Virus Research, 2003

I Introduction
DNA vaccines offer potential solutions to some of the obstacles encountered in developing vaccines for flaviviruses. For example, vaccine interference due to preexisting antibodies to other flaviviruses or to a vaccine vector is not a problem with DNA vaccines. In addition, it should be possible to readily combine DNAs encoding the antigens of a number of flaviviruses to produce multiagent vaccines. Attempts to develop DNA vaccines for flaviviruses have been ongoing for several years, aided by advances in our understanding of the molecular biology of these viruses. Key developments include the molecular cloning and sequence analysis of several medically important flaviviruses beginning with yellow fever virus (Rice et al., 1985); the elucidation of the crystal structure of the envelope (E) glycoprotein of tick-borne encephalitis virus (Heinz et al., 1991); and the many studies of flavivirus gene expression, protein processing and secretion (reviewed in Lindenbach and Rice, 2001).

The E gene is the principal candidate for use in flavivirus DNA vaccines. It encodes the major surface antigen of the virion, which contains immunologically important epitopes (reviewed in Lindenbach and Rice, 2001). Antibodies directed against epitopes on E neutralize the viruses and are important mediators of protective immunity (reviewed in Burke and Monath, 2001). Work with vaccinia virus and other mammalian cell expression systems further showed that interaction of E with another structural protein, prM, is essential for intracellular processing and secretion of E in the correct conformation (reviewed in Burke and Monath, 2001). Consequently, for most DNA vaccine studies, the prM and the E genes have been coexpressed. A few studies have evaluated candidate DNA vaccines encoding nonstructural proteins (NS1 or NS3), because of earlier work demonstrating that these proteins also elicit protective immune responses in animal models (Chen et al., 1999; Lin et al., 1998; Morozova et al., 2000; Schlesinger et al., 1987). In general, studies to date indicate that optimal coexpression of the complete prM and E genes results in the best immunogenicity for flavivirus DNA vaccines.

In addition to considering which flavivirus genes to express, development of effective DNA vaccines requires the consideration of gene promoter and enhancer elements for optimal expression, the vaccine delivery device and the route of inoculation for efficient targeting of antigen processing in cells, and the possible need for accessory factors (i.e., genetic adjuvants), such as cytokine genes or immunostimulatory sequences. Most flavivirus DNA vaccine efforts have been performed using plasmid vectors with a cytomegalovirus (CMV) immediate early promoter to control transcription, although Rous sarcoma virus (RSV) (Chang et al., 2000) and SV40 (Allison et al., 1995) promoters have also been used.

As in many other DNA vaccine studies, the vectors used most frequently in flavivirus DNA vaccine experiments have nucleotides encoding bovine growth hormone polyadenylation signals for transcription termination. For selection in bacteria, either ampicillin or kanamycin resistance genes are included. The ampicillin resistance gene contains more immunostimulatory CpG motifs for mice than does the kanamycin resistance gene (Sato et al., 1996), which might bias some of the studies conducted in mice. The kanamycin resistance gene is more suitable for vaccines destined for clinical studies, because of concerns that the ampicillin gene might be incorporated into pathogenic bacteria when inoculated into humans, thus rendering them resistant to common antibiotic treatment. In contrast, kanamycin and other aminoglycoside antibiotics such as neomycin are not extensively used to treat clinical infections so development of resistant bacteria would be less problematic (FDA, 1996).

A variety of DNA vaccine approaches have been studied in animals, many with promising results. Clinical studies to support the potential of DNA vaccines are currently lacking. In this review we will summarize efforts to develop DNA vaccines for a number of flaviviruses and studies to evaluate them in animal models.

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Respiratory Virus Vaccines
Andrew J. Broadbent, … Kanta Subbarao, in Mucosal Immunology (Fourth Edition), 2015

DNA Influenza Vaccines
DNA vaccines encoding one or several proteins of influenza viruses induce an immune response targeting the encoded proteins (Fynan et al., 1993; Ulmer et al., 1993; Wolff et al., 1990). DNA vaccines can be produced rapidly and at low cost; however, designing DNA vaccines is complex. Over the years, it has been shown that numerous factors play roles in the efficiency of expression, such as the promoter, the G/C content, supercoiling, polyadenylation, and codon optimization (Laddy and Weiner, 2006). In addition, safety remains a concern, as there might be a risk of integration into the host genome (Klinman et al., 1997).

Numerous studies have evaluated DNA vaccines expressing NP, M1, or HA proteins in animal models (Fu et al., 1999; Saha et al., 2006; Tao et al., 2009; Ulmer et al., 1998, 1996a,b). In mice, the administration of DNA vaccines encoding the NP protein of influenza induces a strong CTL response, which correlates with protection against challenge with homologous or heterologous viruses (Ulmer et al., 1993). In addition, one study showed that delivering the vaccine by in vivo electroporation instead of the classical epidermal route also induces protective humoral and cellular immune responses in mice, ferrets, and nonhuman primates (Laddy et al., 2008).

Recently, a phase 1 clinical trial with an adjuvanted plasmid DNA vaccine encoding influenza H5, HA, NP, and M2 elicited T cell responses against HA in the majority of the subjects and against NP and M2 in some (Smith et al., 2010).

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Immune responses to helminths
Subash Babu, Thomas B. Nutman, in Clinical Immunology (Third Edition), 2008

DNA vaccines are made of DNA coding sequences that specify the candidate antigen protein inserted into a bacterial plasmid under the regulation of a eukaryotic promoter. DNA vaccines can be administered by multiple routes and can induce virtually all types of immune response: CD8 T-cell cytotoxicity, CD4 T-cell help and antibodies. In addition, DNA vaccines contain unmethylated DNA motifs that can stimulate the innate immune response through TLR9 and act as a self-adjuvant. DNA and protein vaccines can be administered as a prime-boost regiment with DNA used for priming and protein vaccines used for boosting. DNA and protein vaccines have been used in experimental models of schistosomiasis, filariasis, Strongyloides and hookworm infection. These include the candidate antigens irV5, paramyosin, Sm14, glutathione-S-transferase, triose phosphate isomerase and Sm23 for schistosomiasis, paramyosin, heart shock proteins, ALT-1 and ALT-2 for filariasis, chitinase and ALT-1 for onchocerciasis, Asp-1, Asp-2, metalloprotease-1 for hookworm infection and SS-eat-6 for Strongyloides infection.48

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Schistosomiasis in The People’s Republic of China
S.-B. Chen, … J.-H. Chen, in Advances in Parasitology, 2016

3.3.2 Plasmid DNA vaccines
DNA vaccines use a plasmid containing the gene(s) that code for an immunogenic protein(s) of interest (Zhang et al., 2015). Until recently, no licensed DNA vaccine is commercially available; however, this technology has gained considerable attention, and several products are at various developmental or experimental trial stages, eg, a recombinant plasmid DNA vaccine, pVAX1/SjTGR that is currently being tested in BALB/c mice. The recombinant plasmid, administrated by a ‘gene gun’, has achieved an average protective efficacy assessed as 27.8–38.8% worm reduction and 40.4–44.5% of liver egg count reduction. All animals vaccinated with pVAX1/SjTGR developed significant specific anti-SjTGR antibodies. Moreover, animals immunized by the gene gun exhibited a splenocyte proliferative response, with an increase in IFN-γ and IL-4 cytokines (Cao et al., 2013). Purified vaccine antigens are often poorly immunogenic, even when produced as recombinant subunit vaccines, and require additional components, such as adjuvants, to stimulate protective immunity based on antibodies and effector-T cells. Adjuvants are currently widely used in animal models, but they are rarely used in human. Immune stimulation by cytokines has been successful in the control of S. japonicum infection of poultry as experimental animal (Wei et al., 2008). For example, enhancement of a vaccine-induced immune response was achieved by co-administration of a DNA vaccine encoding for S. japonicum 14 kDa fatty acid binding protein (SjFABP) or S. japonicum 26 kDa GST with IL-18 (Wei et al., 2009). In both cases, significant increase in the humoral immune responses has been reported. In another study, cimetidine (CIM), a histamine-2-receptor antagonist, as an adjuvant, with pEGFP-Sj26GST (the recombinant plasmid containing enhanced green fluorescent protein gene and the gene encoding 26 kDa glutathione S-transferase of S. japonicum) DNA vaccine to immunize mice. The results showed a reduction of both worm and egg burdens in the pEGFP-Sj26GST + CIM group (79.0% and 68.4%, respectively), significantly higher than that in pEGFP-Sj26GST alone group (27.0% and 22.5%, respectively). Compared with the pEGFP-Sj26GST alone group, mice immunized with pEGFP-Sj26GST plus CIM showed an elevated level of IFN-γ and IL-12 and a low level of IL-10 in splenocytes, while the levels of IL-4 and IL-5 showed no difference between the two groups (Li et al., 2011). Wang X reported that by using levamisole (LMS) as an adjuvant enhances cell-mediated immunity in DNA vaccination; VR1012-SjGST-32, in an LMS formulation in the murine challenge model. Compared to controls, the VR1012-SjGST-32 plus LMS reduced worm and egg burdens, as well as, the associated immunopathological complications significantly in liver, apparently associated with a Th1-type response. Together, these results suggest that the LMS as a potential schistosome DNA vaccine adjuvant can be useful for prevention, possibly mediated through the induction of a strong Th1-response (Chen et al., 2012). DNA vaccines have some limitations, since most DNA vaccines are administered by injection, which makes their application difficult in large commercial application. APAMAM dendrimers as a novel vaccine delivery vector will assist in protecting the vaccine against enzymatic degradation and may enhance the immunoreactivity of DNA vaccine and increase the protective effect of the SjC23DNA vaccine against S. japonicum infection (Wang et al., 2014).

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Joan E. Nichols, James W. LeDuc, in Vaccines for Biodefense and Emerging and Neglected Diseases, 2009

DNA Vaccines
DNA vaccines are expressed in situ after DNA vaccination and these vaccines induce immune responses in the form of both humoral and CMI responses, including CTL (Fynan et al., 1993a; Deck et al., 1997; Kodihalli et al., 1999, 2000; Drape et al., 2006). DNA vaccines are comprised simply of E. coli-derived plasmid DNA, are not infectious, do not replicate, and encode only the proteins of interest without production of bacterial proteins. The functional components of the plasmid include a strong promoter system (such as the immediate early promoter of cytomegalovirus), a convenient cloning site for insertion of a gene of interest, a polyadenylation termination sequence, a prokaryotic origin of replication for production in E. coli, and a selectable marker (e.g., ampicillin resistance gene) to facilitate selection of bacterial cells containing the plasmid. Some of the earliest work on DNA vaccines was conducted using influenza as a model system. These studies at least in animals including nonhuman primates, demonstrated production of hemagglutination inhibiting (HI) antibodies and CTL. The potency of DNA vaccines encoding influenza virus antigens in many of these animal studies was demonstrated by the low amounts of DNA required to induce immunity, using either IM injection of the vaccine or by use of the gene gun (Fynan et al., 1993b). Combined immunization with DNA encoding HA (which can generate neutralizing antibodies) and DNA encoding NP and M1 (which can induce broad T-cell responses) may provide a greater breadth of protection than can be obtained with conventional inactivated influenza vaccines and may be useful in humans against influenza (Fynan et al., 1993a; Kodihalli et al., 1999). The first human trial of a DNA vaccine designed to prevent H5N1 avian influenza infection began on December 21, 2006. The vaccine was delivered with a particle-mediated epidermal delivery (PMED) needle-free injection system, which delivers DNA to the epidermal layer of the skin where it enters the cells of the immune network, creating immunity and facilitating both treatment and prevention of disease (Fynan et al., 1993b).

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Viruses as Tools for Vaccine Development
Boriana Marintcheva, in Harnessing the Power of Viruses, 2018 DNA Plasmid/Naked DNA Vaccines
Naked DNA vaccines are composed of plasmid DNA engineered to express a gene of interest, once entered into the host cell. As a nucleic acid, DNA itself has very poor immunogenic properties and is not expected to generate any immune response. Instead, the protein encoded by the plasmid would be expressed by transfected cells and secreted, thus “creating” extracellular antigen or by transfected APC cells, collectively activating both humoral and cellular immune response. As of 2016, several veterinary DNA vaccines have been licensed (for example, anti-West Nile Virus vaccine for horses, anti-Infectious Hematopoietic Necrosis Virus for salmon) and no human DNA vaccines are currently on the market. Human DNA vaccines against several viruses are currently in various stages of clinical trials; for example, influenza A, Ebola, West Nile virus, SARS. Up-to-date information about ongoing trials can be obtained by the clinical trials database run by the National Institutes of Health ( Major safety concerns for DNA vaccines are: (1) the possibility for plasmid DNA integration in the cellular genome, which could potentially inactivate tumor suppressor genes and lead to cancer; (2) the possibility of triggering autoimmune diseases by generation of anti-DNA antibodies; (3) the possibility of spreading antibiotic resistance since antibiotic-based selection markers are used for plasmid production. Available data provide no evidence to support these concerns. The delivery of DNA vaccines is an area of active research experimenting with a wide range of tools, such as DNA guns, liposomes, VLPs, and polymer nanoparticles. Another area of active research is optimization of the protein expression. The biggest advantages of DNA vaccines are that they cannot cause infection of any kind, the plasmids are not transferable and cannot replicate themselves, and thus are very safe. Plasmid DNA is cheap and easy to produce, has a great shelf life, and can be transported/stored easily. The licensing of veterinary DNA vaccines, as well as the current state of the field, suggest that the first human DNA vaccines are around the corner.

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