DNA vaccines: ready for prime time?
TL;DR: A productive future for DNA vaccine technology is suggested as more optimized constructs, better trial designs and improved platforms are being brought into the clinic.
Abstract: Since the discovery, over a decade and a half ago, that genetically engineered DNA can be delivered in vaccine form and elicit an immune response, there has been much progress in understanding the basic biology of this platform. A large amount of data has been generated in preclinical model systems, and more sustained cellular responses and more consistent antibody responses are being observed in the clinic. Four DNA vaccine products have recently been approved, all in the area of veterinary medicine. These results suggest a productive future for this technology as more optimized constructs, better trial designs and improved platforms are being brought into the clinic.
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TL;DR: The challenges for clinical translation of RNA-based therapeutics are discussed, with an emphasis on recent advances in biomaterials and delivery strategies, and an overview of the applications of mRNA-based delivery for protein therapy, gene editing, and vaccination are presented.
564 citations
TL;DR: It is shown that nonviral delivery of a 9-kb self-amplifying RNA encapsulated within an LNP substantially increased immunogenicity compared with delivery of unformulated RNA.
Abstract: Despite more than two decades of research and development on nucleic acid vaccines, there is still no commercial product for human use. Taking advantage of the recent innovations in systemic delivery of short interfering RNA (siRNA) using lipid nanoparticles (LNPs), we developed a self-amplifying RNA vaccine. Here we show that nonviral delivery of a 9-kb self-amplifying RNA encapsulated within an LNP substantially increased immunogenicity compared with delivery of unformulated RNA. This unique vaccine technology was found to elicit broad, potent, and protective immune responses, that were comparable to a viral delivery technology, but without the inherent limitations of viral vectors. Given the many positive attributes of nucleic acid vaccines, our results suggest that a comprehensive evaluation of nonviral technologies to deliver self-amplifying RNA vaccines is warranted.
552 citations
Cites background from "DNA vaccines: ready for prime time?..."
...Approaches include administration of nucleic acids in a naked form (simply formulated in buffer); in combination with lipids, polymers, or other compounds; and by physical techniques such as gene gun and electroporation (EP) (2)....
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...Although plasmid DNA (pDNA) vaccines have proven to be a flexible platform and are broadly effective in small animal models, they have generally lacked potency in human clinical trials (2)....
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...pDNA required for effective immunization of larger animals being 1,000-fold higher than for small species (milligrams versus micrograms) (2)....
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TL;DR: Current research progress on mRNA vaccines is summarized, which have the potential to be quick-manufactured and to become powerful tools against infectious disease and the bright future of their design and applications are highlighted.
Abstract: During the last two decades, there has been broad interest in RNA-based technologies for the development of prophylactic and therapeutic vaccines. Preclinical and clinical trials have shown that mRNA vaccines provide a safe and long-lasting immune response in animal models and humans. In this review, we summarize current research progress on mRNA vaccines, which have the potential to be quick-manufactured and to become powerful tools against infectious disease and we highlight the bright future of their design and applications.
434 citations
Cites background from "DNA vaccines: ready for prime time?..."
...Although promising and with shown safety, well-tolerability and immunogenicity, DNA vaccines were characterized by suboptimal potency in early clinical trials (11)....
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TL;DR: The ability of the current, or second-generation, DNA vaccines to induce more-potent cellular and humoral responses opens up this platform to be examined in both preventative and therapeutic arenas.
Abstract: It was discovered almost 20 years ago that plasmid DNA, when injected into the skin or muscle of mice, could induce immune responses to encoded antigens. Since that time, there has since been much progress in understanding the basic biology behind this deceptively simple vaccine platform and much technological advancement to enhance immune potency. Among these advancements are improved formulations and improved physical methods of delivery, which increase the uptake of vaccine plasmids by cells; optimization of vaccine vectors and encoded antigens; and the development of novel formulations and adjuvants to augment and direct the host immune response. The ability of the current, or second-generation, DNA vaccines to induce more-potent cellular and humoral responses opens up this platform to be examined in both preventative and therapeutic arenas. This review focuses on these advances and discusses both preventive and immunotherapeutic clinical applications.
351 citations
Cites background from "DNA vaccines: ready for prime time?..."
...Formulation and Molecular Adjuvants Formulation of DNA vaccines in microparticles or liposomes has been reported to increase the uptake of plasmid DNA by cells, thereby increasing the immunogenicity of several different vaccines in animal models and humans [7]....
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...For example, consensus immunogens are designed to encode the most commonly occurring amino acid at each position in a sequence, whereas mosaic antigens are designed to encode the most immunogenic regions of an antigen [7]....
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...These efforts include optimization of the antigens encoded by the plasmids to increase antigen expression on a per cell basis, improved formulation, and inclusion of molecular adjuvants to enhance and direct immune responses [7]....
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TL;DR: The rational design of nanomaterials of low immunotoxicity will be discussed, focusing on synthetic nanodevices, with emphasis on both the nanoparticle-forming materials and the embedded cargoes.
Abstract: Nanoscale objects, whether of biologic origin or synthetically created, are being developed into devices for a variety of bionanotechnology diagnostic and pharmaceutical applications. However, the potential immunotoxicity of these nanomaterials and mechanisms by which they may induce adverse reactions have not received sufficient attention. Nanomaterials, depending on their characteristics and compositions, can interact with the immune system in several ways and either enhance or suppress immune system function. Cytokines perform pleiotropic functions to mediate and regulate the immune response and are generally recognized as biomarkers of immunotoxicity. While the specificity and validity of certain cytokines as markers of adverse immune response has been established for chemicals, small and macromolecular drugs, research on their applicability for predicting and monitoring the immunotoxicity of engineered nanomaterials is still ongoing. The goal of this review is to provide guidelines as to important cytokines that can be utilized for evaluating the immunotoxicity of nanomaterials and to highlight the role of those cytokines in mediating adverse reactions, which is of particular importance for the clinical development of nanopharmaceuticals and other nanotechnology-based products. Importantly, the rational design of nanomaterials of low immunotoxicity will be discussed, focusing on synthetic nanodevices, with emphasis on both the nanoparticle-forming materials and the embedded cargoes.
316 citations
References
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TL;DR: The derivation of a number of tissue culture cell lines which secrete anti-sheep red blood cell (SRBC) antibodies is described here, made by fusion of a mouse myeloma and mouse spleen cells from an immunised donor.
Abstract: THE manufacture of predefined specific antibodies by means of permanent tissue culture cell lines is of general interest. There are at present a considerable number of permanent cultures of myeloma cells1,2 and screening procedures have been used to reveal antibody activity in some of them. This, however, is not a satisfactory source of monoclonal antibodies of predefined specificity. We describe here the derivation of a number of tissue culture cell lines which secrete anti-sheep red blood cell (SRBC) antibodies. The cell lines are made by fusion of a mouse myeloma and mouse spleen cells from an immunised donor. To understand the expression and interactions of the Ig chains from the parental lines, fusion experiments between two known mouse myeloma lines were carried out.
19,053 citations
"DNA vaccines: ready for prime time?..." refers background in this paper
...More than 20 years elapsed between Kohler and Millstein's pioneering report of hybridoma technolog...
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01 Jan 2016
TL;DR: This paper critically analyzes the deployment issues of best three proposals considering trade-off between security functions and performance overhead and concludes that none of them is deployable in practical scenario.
Abstract: Border Gateway Protocol (BGP) is the protocol backing the core routing decisions on the Internet. It maintains a table of IP networks or 'prefixes' which designate network reachability among autonomous systems (AS). Point of concern in BGP is its lack of effective security measures which makes Internet vulnerable to different forms of attacks. Many solutions have been proposed till date to combat BGP security issues but not a single one is deployable in practical scenario. Any security proposal with optimal solution should offer adequate security functions, performance overhead and deployment cost. This paper critically analyzes the deployment issues of best three proposals considering trade-off between security functions and performance overhead.
2,691 citations
TL;DR: To generate a viral antigen for presentation to the immune system without the limitations of direct peptide delivery or viral vectors, plasmid DNA encoding influenza A nucleop protein was injected into the quadriceps of BALB/c mice and resulted in the generation of nucleoprotein-specific CTLs.
Abstract: Cytotoxic T lymphocytes (CTLs) specific for conserved viral antigens can respond to different strains of virus, in contrast to antibodies, which are generally strain-specific. The generation of such CTLs in vivo usually requires endogenous expression of the antigen, as occurs in the case of virus infection. To generate a viral antigen for presentation to the immune system without the limitations of direct peptide delivery or viral vectors, plasmid DNA encoding influenza A nucleoprotein was injected into the quadriceps of BALB/c mice. This resulted in the generation of nucleoprotein-specific CTLs and protection from a subsequent challenge with a heterologous strain of influenza A virus, as measured by decreased viral lung titers, inhibition of mass loss, and increased survival.
2,585 citations
"DNA vaccines: ready for prime time?..." refers background in this paper
...(2), including factors to avoid (for example, chi-sites, which are sequences that encourage crossing-over to occur at...
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...transfection by the plasmid vaccine (2) or...
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TL;DR: It is reported that an immune response can be elicited by introducing the gene encoding a protein directly into the skin of mice by using a hand-held form of the biolistic system.
Abstract: To produce an immune reaction against a foreign protein usually requires purification of that protein, which is then injected into an animal. The isolation of enough pure protein is time-consuming and sometimes difficult. Here we report that such a response can also be elicited by introducing the gene encoding a protein directly into the skin of mice. This is achieved using a hand-held form of the biolistic system which can propel DNA-coated gold microprojectiles directly into cells in the living animal. Genetic immunization may be time- and labour-saving in producing antibodies and may offer a unique method for vaccination.
1,647 citations
"DNA vaccines: ready for prime time?..." refers background in this paper
...transcriptional elements on the plasmid backbone (1); strategies to improve protein expression of the gene of interest...
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TL;DR: The HCMV enhancer, which seems to have little cell type or species preference, is severalfold more active than the SV40 enhancers, a property that makes it a useful component of eukaryotic expression vectors.
1,336 citations
"DNA vaccines: ready for prime time?..." refers background in this paper
...However, more recently, promoters from non-carcinogenic sources that are equally effective have been used, including one from human cytomegalovirus (CMV...
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