Special Issue "DNA Vaccines"

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A special issue of Vaccines (ISSN 2076-393X).

Deadline for manuscript submissions: closed (15 May 2013)

Special Issue Editors

Guest Editor
Prof. Dr. Margaret A. Liu (Website)

1 ProTherImmune, 3656 Happy Valley Road Lafayette, CA 94549, USA
2 Karolinska Institute, Stockholm SE-17177, Sweden
3. Adjunct Professor, Department of Microbiology and Immunology, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143 USA
Fax: +1 925 299 2959
Interests: vaccine technologies; DNA vaccines; cellular immune responses; HIV Vvccines; global health
Co-Guest Editor
Prof. Dr. Britta Wahren (Website)

Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet Center for HIV research, Nobel´s Road 16, 171 77 Stockholm, Sweden
Interests: infectious diseases; virology; tumor biology; HIV vaccines; genetic vaccines

Special Issue Information

Dear Colleagues,

During the last few years, there has been immense progress in the field of gene-based vaccines. This has been a result of new and better vectors, improved expression constructs, different types of delivery methods and devices, and it may be said, selection of optimal diseases/antigens and vaccinees. Several products have been licensed for veterinary applications, including infectious diseases and cancer. New human clinical trials have been initiated, and a number of phase 1-2 trials concluded. The present issue on “Research progress for gene-based vaccines” will bring together primary data and up-to-date summaries of break-throughs in using DNA plasmids for vaccines and immunotherapies. It will also show the possibilities of gene therapy, for which there is one licensed veterinary product and a different human one. To exemplify the progress, the situation for several severe infectious diseases and tumors will be depicted together with future views for further translation into the clinic.

It is 20 years since the first data on DNA vaccines were publicly presented at Cold Spring Harbor, 1992. Clinical trials of DNA vaccines are in progress for many diseases including HIV, HCV, malaria, influenza, tuberculosis and tumors (colo-rectal, prostate, melanoma). These include plasmid constructs used as a prime for boosting with other types of vaccines.

Prof. Dr. Margaret A. Liu
Prof. Dr. Britta Wahren
Guest Editors

Submission

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are refereed through a peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Vaccines is an international peer-reviewed Open Access quarterly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 300 CHF (Swiss Francs). English correction and/or formatting fees of 250 CHF (Swiss Francs) will be charged in certain cases for those articles accepted for publication that require extensive additional formatting and/or English corrections.

Keywords

  • DNA vaccine
  • RNA vaccine
  • infectious diseases
  • autoimmune diseases
  • allergy
  • immune mechanisms
  • antibodies
  • T cells
  • innate immunity
  • delivery technology
  • prime-boost
  • adjuvants
  • electroporation
  • prophylaxis

Published Papers (17 papers)

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Editorial

Jump to: Research, Review, Other

Open AccessEditorial DNA Vaccines: Recent Developments and the Future
Vaccines 2014, 2(4), 785-796; doi:10.3390/vaccines2040785
Received: 27 September 2014 / Revised: 29 September 2014 / Accepted: 29 September 2014 / Published: 27 October 2014
Cited by 4 | PDF Full-text (180 KB) | HTML Full-text | XML Full-text
Abstract
This special issue is focused on DNA vaccines, marking the two decades since the first demonstration of pre-clinical protection was published in Science (Ulmer et al.; Heterologous protection against influenza by injection of DNA encoding a viral protein. 1993). This introductory [...] Read more.
This special issue is focused on DNA vaccines, marking the two decades since the first demonstration of pre-clinical protection was published in Science (Ulmer et al.; Heterologous protection against influenza by injection of DNA encoding a viral protein. 1993). This introductory article provides an overview of the field and highlights the observations of the articles in this special issue while placing them in the context of other recent publications. Full article
(This article belongs to the Special Issue DNA Vaccines)

Research

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Open AccessArticle Immunotherapy with an HIV-DNA Vaccine in Children and Adults
Vaccines 2014, 2(3), 563-580; doi:10.3390/vaccines2030563
Received: 27 February 2014 / Revised: 26 June 2014 / Accepted: 27 June 2014 / Published: 17 July 2014
Cited by 3 | PDF Full-text (1114 KB) | HTML Full-text | XML Full-text
Abstract
Therapeutic HIV immunization is intended to induce new HIV-specific cellular immune responses and to reduce viral load, possibly permitting extended periods without antiretroviral drugs. A multigene, multi-subtype A, B, C HIV-DNA vaccine (HIVIS) has been used in clinical trials in both children [...] Read more.
Therapeutic HIV immunization is intended to induce new HIV-specific cellular immune responses and to reduce viral load, possibly permitting extended periods without antiretroviral drugs. A multigene, multi-subtype A, B, C HIV-DNA vaccine (HIVIS) has been used in clinical trials in both children and adults with the aim of improving and broadening the infected individuals’ immune responses. Despite the different country locations, different regimens and the necessary variations in assays performed, this is, to our knowledge, the first attempt to compare children’s and adults’ responses to a particular HIV vaccine. Ten vertically HIV-infected children aged 4–16 years were immunized during antiretroviral therapy (ART). Another ten children were blindly recruited as controls. Both groups continued their antiretroviral treatment during and after vaccinations. Twelve chronically HIV-infected adults were vaccinated, followed by repeated structured therapy interruptions (STI) of their antiretroviral treatment. The adult group included four controls, receiving placebo vaccinations. The HIV-DNA vaccine was generally well tolerated, and no serious adverse events were registered in any group. In the HIV-infected children, an increased specific immune response to Gag and RT proteins was detected by antigen-specific lymphoproliferation. Moreover, the frequency of HIV-specific CD8+ T-cell lymphocytes releasing perforin was significantly higher in the vaccinees than the controls. In the HIV-infected adults, increased CD8+ T-cell responses to Gag, RT and viral protease peptides were detected. No augmentation of HIV-specific lymphoproliferative responses were detected in adults after vaccination. In conclusion, the HIV-DNA vaccine can elicit new HIV-specific cellular immune responses, particularly to Gag antigens, in both HIV-infected children and adults. Vaccinated children mounted transient new HIV-specific immune responses, including both CD4+ T-cell lymphoproliferation and late CD8+ T-cell responses. In the adult cohort, primarily CD8+ T-cell responses related to MHC class I alleles were noted. However, no clinical benefits with respect to viral load reduction were ascribable to the vaccinations alone. No severe adverse effects related to the vaccine were found in either cohort, and no virological failures or drug resistances were detected. Full article
(This article belongs to the Special Issue DNA Vaccines)
Open AccessArticle Co-Administration of Molecular Adjuvants Expressing NF-Kappa B Subunit p65/RelA or Type-1 Transactivator T-bet Enhance Antigen Specific DNA Vaccine-Induced Immunity
Vaccines 2014, 2(2), 196-215; doi:10.3390/vaccines2020196
Received: 27 November 2013 / Revised: 31 January 2014 / Accepted: 28 February 2014 / Published: 25 March 2014
Cited by 3 | PDF Full-text (1452 KB) | HTML Full-text | XML Full-text
Abstract
DNA vaccine-induced immunity can be enhanced by the co-delivery of synthetic gene-encoding molecular adjuvants. Many of these adjuvants have included cytokines, chemokines or co-stimulatory molecules that have been demonstrated to enhance vaccine-induced immunity by increasing the magnitude or type of immune responses [...] Read more.
DNA vaccine-induced immunity can be enhanced by the co-delivery of synthetic gene-encoding molecular adjuvants. Many of these adjuvants have included cytokines, chemokines or co-stimulatory molecules that have been demonstrated to enhance vaccine-induced immunity by increasing the magnitude or type of immune responses and/or protective efficacy. In this way, through the use of adjuvants, immune responses can be highly customizable and functionally tailored for optimal efficacy against pathogen specific (i.e., infectious agent) or non-pathogen (i.e., cancer) antigens. In the novel study presented here, we examined the use of cellular transcription factors as molecular adjuvants. Specifically the co-delivery of (a) RelA, a subunit of the NF-κB transcription complex or (b) T-bet, a Th1-specific T box transcription factor, along with a prototypical DNA vaccine expressing HIV-1 proteins was evaluated. As well, all of the vaccines and adjuvants were administered to mice using in vivo electroporation (EP), a technology demonstrated to dramatically increase plasmid DNA transfection and subsequent transgene expression with concomitant enhancement of vaccine induced immune responses. As such, this study demonstrated that co-delivery of either adjuvant resulted in enhanced T and B cell responses, specifically characterized by increased T cell numbers, IFN-γ production, as well as enhanced antibody responses. This study demonstrates the use of cellular transcription factors as adjuvants for enhancing DNA vaccine-induced immunity. Full article
(This article belongs to the Special Issue DNA Vaccines)
Open AccessArticle Increasing the Vaccine Potential of Live M. bovis BCG by Coadministration with Plasmid DNA Encoding a Tuberculosis Prototype Antigen
Vaccines 2014, 2(1), 181-195; doi:10.3390/vaccines2010181
Received: 23 January 2014 / Revised: 12 February 2014 / Accepted: 19 February 2014 / Published: 5 March 2014
Cited by 3 | PDF Full-text (810 KB) | HTML Full-text | XML Full-text
Abstract
The attenuated live M. bovis Bacille-Calmette-Guérin (BCG) is still the sole vaccine used against tuberculosis, but confers only variable efficacy against adult pulmonary tuberculosis (TB). Though no clear explanation for this limited efficacy has been given, different hypotheses have been advanced, [...] Read more.
The attenuated live M. bovis Bacille-Calmette-Guérin (BCG) is still the sole vaccine used against tuberculosis, but confers only variable efficacy against adult pulmonary tuberculosis (TB). Though no clear explanation for this limited efficacy has been given, different hypotheses have been advanced, such as the waning of memory T-cell responses, a reduced antigenic repertoire and the inability to induce effective CD8+ T-cell responses, which are known to be essential for latent tuberculosis control. In this study, a new BCG-based vaccination protocol was studied, in which BCG was formulated in combination with a plasmid DNA vaccine. As BCG is routinely administered to neonates, we have evaluated a more realistic approach of a simultaneous intradermal coadministration of BCG with pDNA encoding the prototype antigen, PPE44. Strongly increased T- and B-cell responses were observed with this protocol in C57BL/6 mice when compared to the administration of only BCG or in combination with an empty pDNA vector, as measured by Th1-type spleen cell cytokine secretion, specific IgG antibodies, as well as specific IFN-γ producing/cytolytic-CD8+ T-cells. Moreover, we observed a bystander activation induced by the coding plasmid, resulting in increased immune responses against other non-plasmid encoded, but BCG-expressed, antigens. In all, these results provide a proof of concept for a new TB vaccine, based on a BCG-plasmid DNA combination. Full article
(This article belongs to the Special Issue DNA Vaccines)
Open AccessArticle Pilot Study on the Use of DNA Priming Immunization to Enhance Y. pestis LcrV-Specific B Cell Responses Elicited by a Recombinant LcrV Protein Vaccine
Vaccines 2014, 2(1), 36-48; doi:10.3390/vaccines2010036
Received: 11 October 2013 / Revised: 26 November 2013 / Accepted: 5 December 2013 / Published: 27 December 2013
Cited by 3 | PDF Full-text (653 KB) | HTML Full-text | XML Full-text
Abstract
Recent studies indicate that DNA immunization is powerful in eliciting antigen-specific antibody responses in both animal and human studies. However, there is limited information on the mechanism of this effect. In particular, it is not known whether DNA immunization can also enhance [...] Read more.
Recent studies indicate that DNA immunization is powerful in eliciting antigen-specific antibody responses in both animal and human studies. However, there is limited information on the mechanism of this effect. In particular, it is not known whether DNA immunization can also enhance the development of antigen-specific B cell development. In this report, a pilot study was conducted using plague LcrV immunogen as a model system to determine whether DNA immunization is able to enhance LcrV-specific B cell development in mice. Plague is an acute and often fatal infectious disease caused by Yersinia pestis (Y. pestis). Humoral immune responses provide critical protective immunity against plague. Previously, we demonstrated that a DNA vaccine expressing LcrV antigen can protect mice from lethal mucosal challenge. In the current study, we further evaluated whether the use of a DNA priming immunization is able to enhance the immunogenicity of a recombinant LcrV protein vaccine, and in particular, the development of LcrV-specific B cells. Our data indicate that DNA immunization was able to elicit high-level LcrV antibody responses when used alone or as part of a prime-boost immunization approach. Most significantly, DNA immunization was also able to increase the levels of LcrV-specific B cell development. The finding that DNA immunization can enhance antigen-specific B cell responses is highly significant and will help guide similar studies in other model antigen systems. Full article
(This article belongs to the Special Issue DNA Vaccines)
Open AccessArticle Evaluation of Different DNA Vaccines against Porcine Reproductive and Respiratory Syndrome (PRRS) in Pigs
Vaccines 2013, 1(4), 463-480; doi:10.3390/vaccines1040463
Received: 30 July 2013 / Revised: 10 September 2013 / Accepted: 9 October 2013 / Published: 18 October 2013
Cited by 1 | PDF Full-text (459 KB) | HTML Full-text | XML Full-text
Abstract
In veterinary medicine, there have been different experiences with the plasmid DNA vaccination. In this area and with the hypothesis to demonstrate the effectiveness of different plasmids encoding porcine respiratory and reproductive syndrome (PRRS), five DNA vaccines against PRRS were evaluated for [...] Read more.
In veterinary medicine, there have been different experiences with the plasmid DNA vaccination. In this area and with the hypothesis to demonstrate the effectiveness of different plasmids encoding porcine respiratory and reproductive syndrome (PRRS), five DNA vaccines against PRRS were evaluated for their innocuity and efficacy in pigs. Eighteen animals were divided into five groups which were injected with five (A, B, C, D, E) different DNA vaccines. Albeit, none of the proposed vaccines were able to protect the animals against PRRS virus. Only vaccines A and B were able to reduce the clinical signs of the infection. ELISA IgM were detected 30 days after the first vaccination in the pigs injected by Vaccine A or B. ELISA IgG were detected 90 days after the first vaccination in the pigs injected by Vaccine B or C. Neutralizing antibody were detected Post Challenge Days 61 (PCD) in all groups. In the pigs inoculated with Vaccine C, IFN-g were detected 90 days after first vaccination, and after challenge exposure they increased. In the other groups, the IFN-g were detected after challenge infection. Pigs injected with each of the vaccines A, B, C, D and E showed a significantly higher level of CD4CD8+ lymphocytes (p < 0.001) after infection in comparison with their controls. Full article
(This article belongs to the Special Issue DNA Vaccines)
Open AccessArticle DNA-Encoded Flagellin Activates Toll-Like Receptor 5 (TLR5), Nod-like Receptor Family CARD Domain-Containing Protein 4 (NRLC4), and Acts as an Epidermal, Systemic, and Mucosal-Adjuvant
Vaccines 2013, 1(4), 415-443; doi:10.3390/vaccines1040415
Received: 18 July 2013 / Revised: 27 August 2013 / Accepted: 30 August 2013 / Published: 25 September 2013
Cited by 1 | PDF Full-text (940 KB) | HTML Full-text | XML Full-text
Abstract
Eliciting effective immune responses using non-living/replicating DNA vaccines is a significant challenge. We have previously shown that ballistic dermal plasmid DNA-encoded flagellin (FliC) promotes humoral as well as cellular immunity to co-delivered antigens. Here, we observe that a plasmid encoding secreted FliC [...] Read more.
Eliciting effective immune responses using non-living/replicating DNA vaccines is a significant challenge. We have previously shown that ballistic dermal plasmid DNA-encoded flagellin (FliC) promotes humoral as well as cellular immunity to co-delivered antigens. Here, we observe that a plasmid encoding secreted FliC (pFliC(-gly)) produces flagellin capable of activating two innate immune receptors known to detect flagellin; Toll-like Receptor 5 (TLR5) and Nod-like Receptor family CARD domain-containing protein 4 (NRLC4). To test the ability of pFliC(-gly) to act as an adjuvant we immunized mice with plasmid encoding secreted FliC (pFliC(-gly)) and plasmid encoding a model antigen (ovalbumin) by three different immunization routes representative of dermal, systemic, and mucosal tissues. By all three routes we observed increases in antigen-specific antibodies in serum as well as MHC Class I-dependent cellular immune responses when pFliC(-gly) adjuvant was added. Additionally, we were able to induce mucosal antibody responses and Class II-dependent cellular immune responses after mucosal vaccination with pFliC(-gly). Humoral immune responses elicited by heterologus prime-boost immunization with a plasmid encoding HIV-1 from gp160 followed by protein boosting could be enhanced by use of pFliC(-gly). We also observed enhancement of cross-clade reactive IgA as well as a broadening of B cell epitope reactivity. These observations indicate that plasmid-encoded secreted flagellin can activate multiple innate immune responses and function as an adjuvant to non-living/replicating DNA immunizations. Moreover, the capacity to elicit mucosal immune responses, in addition to dermal and systemic properties, demonstrates the potential of flagellin to be used with vaccines designed to be delivered by various routes. Full article
(This article belongs to the Special Issue DNA Vaccines)
Open AccessArticle Elucidating the Kinetics of Expression and Immune Cell Infiltration Resulting from Plasmid Gene Delivery Enhanced by Surface Dermal Electroporation
Vaccines 2013, 1(3), 384-397; doi:10.3390/vaccines1030384
Received: 16 July 2013 / Revised: 13 August 2013 / Accepted: 21 August 2013 / Published: 28 August 2013
Cited by 6 | PDF Full-text (837 KB) | HTML Full-text | XML Full-text
Abstract
The skin is an attractive tissue for vaccination in a clinical setting due to the accessibility of the target, the ease of monitoring and most importantly the immune competent nature of the dermal tissue. While skin electroporation offers an exciting and novel [...] Read more.
The skin is an attractive tissue for vaccination in a clinical setting due to the accessibility of the target, the ease of monitoring and most importantly the immune competent nature of the dermal tissue. While skin electroporation offers an exciting and novel future methodology for the delivery of DNA vaccines in the clinic, little is known about the actual mechanism of the approach and the elucidation of the resulting immune responses. To further understand the mechanism of this platform, the expression kinetics and localization of a reporter plasmid delivered via a surface dermal electroporation (SEP) device as well as the effect that this treatment would have on the resident immune cells in that tissue was investigated. Initially a time course (day 0 to day 21) of enhanced gene delivery with electroporation (EP) was performed to observe the localization of green fluorescent protein (GFP) expression and the kinetics of its appearance as well as clearance. Using gross imaging, GFP expression was not detected on the surface of the skin until 8 h post treatment. However, histological analysis by fluorescent microscopy revealed GFP positive cells as early as 1 h after plasmid delivery and electroporation. Peak GFP expression was observed at 24 h and the expression was maintained in skin for up to seven days. Using an antibody specific for a keratinocyte cell surface marker, reporter gene positive keratinocytes in the epidermis were identified. H&E staining of treated skin sections demonstrated an influx of monocytes and granulocytes at the EP site starting at 4 h and persisting up to day 14 post treatment. Immunological staining revealed a significant migration of lymphocytic cells to the EP site, congregating around cells expressing the delivered antigen. In conclusion, this study provides insights into the expression kinetics following EP enhanced DNA delivery targeting the dermal space. These findings may have implications in the future to design efficient DNA vaccination strategies for the clinic. Full article
(This article belongs to the Special Issue DNA Vaccines)
Open AccessArticle Enhanced Delivery and Potency of Self-Amplifying mRNA Vaccines by Electroporation in Situ
Vaccines 2013, 1(3), 367-383; doi:10.3390/vaccines1030367
Received: 26 June 2013 / Revised: 12 August 2013 / Accepted: 14 August 2013 / Published: 22 August 2013
Cited by 6 | PDF Full-text (1824 KB) | HTML Full-text | XML Full-text
Abstract
Nucleic acid-based vaccines such as viral vectors, plasmid DNA (pDNA), and mRNA are being developed as a means to address limitations of both live-attenuated and subunit vaccines. DNA vaccines have been shown to be potent in a wide variety of animal species [...] Read more.
Nucleic acid-based vaccines such as viral vectors, plasmid DNA (pDNA), and mRNA are being developed as a means to address limitations of both live-attenuated and subunit vaccines. DNA vaccines have been shown to be potent in a wide variety of animal species and several products are now licensed for commercial veterinary but not human use. Electroporation delivery technologies have been shown to improve the generation of T and B cell responses from synthetic DNA vaccines in many animal species and now in humans. However, parallel RNA approaches have lagged due to potential issues of potency and production. Many of the obstacles to mRNA vaccine development have recently been addressed, resulting in a revival in the use of non-amplifying and self-amplifying mRNA for vaccine and gene therapy applications. In this paper, we explore the utility of EP for the in vivo delivery of large, self-amplifying mRNA, as measured by reporter gene expression and immunogenicity of genes encoding HIV envelope protein. These studies demonstrated that EP delivery of self-amplifying mRNA elicited strong and broad immune responses in mice, which were comparable to those induced by EP delivery of pDNA. Full article
(This article belongs to the Special Issue DNA Vaccines)
Open AccessArticle Optimization of HIV-1 Envelope DNA Vaccine Candidates within Three Different Animal Models, Guinea Pigs, Rabbits and Cynomolgus Macaques
Vaccines 2013, 1(3), 305-327; doi:10.3390/vaccines1030305
Received: 16 May 2013 / Revised: 5 July 2013 / Accepted: 10 July 2013 / Published: 19 July 2013
Cited by 5 | PDF Full-text (724 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
HIV-1 DNA vaccines have many advantageous features. Evaluation of HIV-1 vaccine candidates often starts in small animal models before macaque and human trials. Here, we selected and optimized DNA vaccine candidates through systematic testing in rabbits for the induction of broadly neutralizing [...] Read more.
HIV-1 DNA vaccines have many advantageous features. Evaluation of HIV-1 vaccine candidates often starts in small animal models before macaque and human trials. Here, we selected and optimized DNA vaccine candidates through systematic testing in rabbits for the induction of broadly neutralizing antibodies (bNAb). We compared three different animal models: guinea pigs, rabbits and cynomolgus macaques. Envelope genes from the prototype isolate HIV-1 Bx08 and two elite neutralizers were included. Codon-optimized genes, encoded secreted gp140 or membrane bound gp150, were modified for expression of stabilized soluble trimer gene products, and delivered individually or mixed. Specific IgG after repeated i.d. inoculations with electroporation confirmed in vivo expression and immunogenicity. Evaluations of rabbits and guinea pigs displayed similar results. The superior DNA construct in rabbits was a trivalent mix of non-modified codon-optimized gp140 envelope genes. Despite NAb responses with some potency and breadth in guinea pigs and rabbits, the DNA vaccinated macaques displayed less bNAb activity. It was concluded that a trivalent mix of non-modified gp140 genes from rationally selected clinical isolates was, in this study, the best option to induce high and broad NAb in the rabbit model, but this optimization does not directly translate into similar responses in cynomolgus macaques. Full article
(This article belongs to the Special Issue DNA Vaccines)
Open AccessArticle Enhanced Efficacy of a Codon-Optimized DNA Vaccine Encoding the Glycoprotein Precursor Gene of Lassa Virus in a Guinea Pig Disease Model When Delivered by Dermal Electroporation
Vaccines 2013, 1(3), 262-277; doi:10.3390/vaccines1030262
Received: 31 May 2013 / Revised: 8 July 2013 / Accepted: 10 July 2013 / Published: 18 July 2013
Cited by 4 | PDF Full-text (512 KB) | HTML Full-text | XML Full-text
Abstract
Lassa virus (LASV) causes a severe, often fatal, hemorrhagic fever endemic to West Africa. Presently, there are no FDA-licensed medical countermeasures for this disease. In a pilot study, we constructed a DNA vaccine (pLASV-GPC) that expressed the LASV glycoprotein precursor gene (GPC). [...] Read more.
Lassa virus (LASV) causes a severe, often fatal, hemorrhagic fever endemic to West Africa. Presently, there are no FDA-licensed medical countermeasures for this disease. In a pilot study, we constructed a DNA vaccine (pLASV-GPC) that expressed the LASV glycoprotein precursor gene (GPC). This plasmid was used to vaccinate guinea pigs (GPs) using intramuscular electroporation as the delivery platform. Vaccinated GPs were protected from lethal infection (5/6) with LASV compared to the controls. However, vaccinated GPs experienced transient viremia after challenge, although lower than the mock-vaccinated controls. In a follow-on study, we developed a new device that allowed for both the vaccine and electroporation pulse to be delivered to the dermis. We also codon-optimized the GPC sequence of the vaccine to enhance expression in GPs. Together, these innovations resulted in enhanced efficacy of the vaccine. Unlike the pilot study where neutralizing titers were not detected until after virus challenge, modest neutralizing titers were detected in guinea pigs before challenge, with escalating titers detected after challenge. The vaccinated GPs were never ill and were not viremic at any timepoint. The combination of the codon-optimized vaccine and dermal electroporation delivery is a worthy candidate for further development. Full article
(This article belongs to the Special Issue DNA Vaccines)

Review

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Open AccessReview HIV DNA Vaccine: Stepwise Improvements Make a Difference
Vaccines 2014, 2(2), 354-379; doi:10.3390/vaccines2020354
Received: 21 February 2014 / Revised: 11 April 2014 / Accepted: 18 April 2014 / Published: 14 May 2014
Cited by 8 | PDF Full-text (821 KB) | HTML Full-text | XML Full-text
Abstract
Inefficient DNA delivery methods and low expression of plasmid DNA have been major obstacles for the use of plasmid DNA as vaccine for HIV/AIDS. This review describes successful efforts to improve DNA vaccine methodology over the past ~30 years. DNA vaccination, either [...] Read more.
Inefficient DNA delivery methods and low expression of plasmid DNA have been major obstacles for the use of plasmid DNA as vaccine for HIV/AIDS. This review describes successful efforts to improve DNA vaccine methodology over the past ~30 years. DNA vaccination, either alone or in combination with other methods, has the potential to be a rapid, safe, and effective vaccine platform against AIDS. Recent clinical trials suggest the feasibility of its translation to the clinic. Full article
(This article belongs to the Special Issue DNA Vaccines)
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Open AccessReview DNA/MVA Vaccines for HIV/AIDS
Vaccines 2014, 2(1), 160-178; doi:10.3390/vaccines2010160
Received: 6 January 2014 / Revised: 31 January 2014 / Accepted: 6 February 2014 / Published: 28 February 2014
Cited by 2 | PDF Full-text (827 KB) | HTML Full-text | XML Full-text
Abstract
Since the initial proof-of-concept studies examining the ability of antigen-encoded plasmid DNA to serve as an immunogen, DNA vaccines have evolved as a clinically safe and effective platform for priming HIV-specific cellular and humoral responses in heterologous “prime-boost” vaccination regimens. Direct injection [...] Read more.
Since the initial proof-of-concept studies examining the ability of antigen-encoded plasmid DNA to serve as an immunogen, DNA vaccines have evolved as a clinically safe and effective platform for priming HIV-specific cellular and humoral responses in heterologous “prime-boost” vaccination regimens. Direct injection of plasmid DNA into the muscle induces T- and B-cell responses against foreign antigens. However, the insufficient magnitude of this response has led to the development of approaches for enhancing the immunogenicity of DNA vaccines. The last two decades have seen significant progress in the DNA-based vaccine platform with optimized plasmid constructs, improved delivery methods, such as electroporation, the use of molecular adjuvants and novel strategies combining DNA with viral vectors and subunit proteins. These innovations are paving the way for the clinical application of DNA-based HIV vaccines. Here, we review preclinical studies on the DNA-prime/modified vaccinia Ankara (MVA)-boost vaccine modality for HIV. There is a great deal of interest in enhancing the immunogenicity of DNA by engineering DNA vaccines to co-express immune modulatory adjuvants. Some of these adjuvants have demonstrated encouraging results in preclinical and clinical studies, and these data will be examined, as well. Full article
(This article belongs to the Special Issue DNA Vaccines)
Open AccessReview Recent Developments in Preclinical DNA Vaccination
Vaccines 2014, 2(1), 89-106; doi:10.3390/vaccines2010089
Received: 15 October 2013 / Revised: 22 November 2013 / Accepted: 26 November 2013 / Published: 13 January 2014
Cited by 8 | PDF Full-text (381 KB) | HTML Full-text | XML Full-text
Abstract
The advantages of genetic immunization of the new vaccine using plasmid DNAs are multifold. For example, it is easy to generate plasmid DNAs, increase their dose during the manufacturing process, and sterilize them. Furthermore, they can be stored for a long period [...] Read more.
The advantages of genetic immunization of the new vaccine using plasmid DNAs are multifold. For example, it is easy to generate plasmid DNAs, increase their dose during the manufacturing process, and sterilize them. Furthermore, they can be stored for a long period of time upon stabilization, and their protein encoding sequences can be easily modified by employing various DNA-manipulation techniques. Although DNA vaccinations strongly increase Th1-mediated immune responses in animals, several problems persist. One is about their weak immunogenicity in humans. To overcome this problem, various genetic adjuvants, electroporation, and prime-boost methods have been developed preclinically, which are reviewed here. Full article
(This article belongs to the Special Issue DNA Vaccines)
Open AccessReview Innate Immune Signaling by, and Genetic Adjuvants for DNA Vaccination
Vaccines 2013, 1(3), 278-292; doi:10.3390/vaccines1030278
Received: 13 June 2013 / Revised: 6 July 2013 / Accepted: 9 July 2013 / Published: 18 July 2013
Cited by 10 | PDF Full-text (685 KB) | HTML Full-text | XML Full-text
Abstract
DNA vaccines can induce both humoral and cellular immune responses. Although some DNA vaccines are already licensed for infectious diseases in animals, they are not licensed for human use because the risk and benefit of DNA vaccines is still controversial. Indeed, in [...] Read more.
DNA vaccines can induce both humoral and cellular immune responses. Although some DNA vaccines are already licensed for infectious diseases in animals, they are not licensed for human use because the risk and benefit of DNA vaccines is still controversial. Indeed, in humans, the immunogenicity of DNA vaccines is lower than that of other traditional vaccines. To develop the use of DNA vaccines in the clinic, various approaches are in progress to enhance or improve the immunogenicity of DNA vaccines. Recent studies have shown that immunogenicity of DNA vaccines are regulated by innate immune responses via plasmid DNA recognition through the STING-TBK1 signaling cascade. Similarly, molecules that act as dsDNA sensors that activate innate immune responses through STING-TBK1 have been identified and used as genetic adjuvants to enhance DNA vaccine immunogenicity in mouse models. However, the mechanisms that induce innate immune responses by DNA vaccines are still unclear. In this review, we will discuss innate immune signaling upon DNA vaccination and genetic adjuvants of innate immune signaling molecules. Full article
(This article belongs to the Special Issue DNA Vaccines)
Open AccessReview Vector Design for Improved DNA Vaccine Efficacy, Safety and Production
Vaccines 2013, 1(3), 225-249; doi:10.3390/vaccines1030225
Received: 14 May 2013 / Revised: 12 June 2013 / Accepted: 18 June 2013 / Published: 25 June 2013
Cited by 7 | PDF Full-text (653 KB) | HTML Full-text | XML Full-text
Abstract
DNA vaccination is a disruptive technology that offers the promise of a new rapidly deployed vaccination platform to treat human and animal disease with gene-based materials. Innovations such as electroporation, needle free jet delivery and lipid-based carriers increase transgene expression and immunogenicity [...] Read more.
DNA vaccination is a disruptive technology that offers the promise of a new rapidly deployed vaccination platform to treat human and animal disease with gene-based materials. Innovations such as electroporation, needle free jet delivery and lipid-based carriers increase transgene expression and immunogenicity through more effective gene delivery. This review summarizes complementary vector design innovations that, when combined with leading delivery platforms, further enhance DNA vaccine performance. These next generation vectors also address potential safety issues such as antibiotic selection, and increase plasmid manufacturing quality and yield in exemplary fermentation production processes. Application of optimized constructs in combination with improved delivery platforms tangibly improves the prospect of successful application of DNA vaccination as prophylactic vaccines for diverse human infectious disease targets or as therapeutic vaccines for cancer and allergy. Full article
(This article belongs to the Special Issue DNA Vaccines)
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Other

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Open AccessCase Report Clinical Development of a Cytomegalovirus DNA Vaccine: From Product Concept to Pivotal Phase 3 Trial
Vaccines 2013, 1(4), 398-414; doi:10.3390/vaccines1040398
Received: 10 July 2013 / Revised: 23 August 2013 / Accepted: 28 August 2013 / Published: 25 September 2013
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Abstract
2013 marks a milestone year for plasmid DNA vaccine development as a first-in-class cytomegalovirus (CMV) DNA vaccine enters pivotal phase 3 testing. This vaccine consists of two plasmids expressing CMV antigens glycoprotein B (gB) and phosphoprotein 65 (pp65) formulated with a CRL1005 [...] Read more.
2013 marks a milestone year for plasmid DNA vaccine development as a first-in-class cytomegalovirus (CMV) DNA vaccine enters pivotal phase 3 testing. This vaccine consists of two plasmids expressing CMV antigens glycoprotein B (gB) and phosphoprotein 65 (pp65) formulated with a CRL1005 poloxamer and benzalkonium chloride (BAK) delivery system designed to enhance plasmid expression. The vaccine’s planned initial indication under investigation is for prevention of CMV reactivation in CMV-seropositive (CMV+) recipients of an allogeneic hematopoietic stem cell transplant (HCT). A randomized, double-blind placebo-controlled phase 2 proof-of-concept study provided initial evidence of the safety of this product in CMV+ HCT recipients who underwent immune ablation conditioning regimens. This study revealed a significant reduction in viral load endpoints and increased frequencies of pp65-specific interferon-γ-producing T cells in vaccine recipients compared to placebo recipients. The results of this endpoint-defining trial provided the basis for defining the primary and secondary endpoints of a global phase 3 trial in HCT recipients. A case study is presented here describing the development history of this vaccine from product concept to initiation of the phase 3 trial. Full article
(This article belongs to the Special Issue DNA Vaccines)

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