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  • Review Article
  • Published:

DNA vaccines: ready for prime time?

Nature Reviews Genetics volume 9, pages 776–788 (2008)Cite this article

Key Points

  • Since the initial discovery, over a decade and a half ago, that genetically engineered DNA can be delivered in vaccine form and can elicit an immune response, there has been a great deal of progress in understanding the basic biology of this platform.

  • Data from preclinical studies using DNA vaccine technology has generated a large amount of excitement, because protective immunity was induced by platforms against a broad range of virus families.

  • The initial development of DNA vaccines in larger animals and human studies showed that DNA is well tolerated and has an excellent safety record.

  • Clinical studies of first-generation vaccines, primarily consisting of naked DNA, showed that this platform induces only low levels of immunity. The status of these vaccines as a stand-alone platform was thus jeopardized, demonstrating the need for improvements in delivery technology and continued optimization of 'prime-boost' strategies.

  • Recent studies have generated new leads from basic research on insert design, RNA structure, variation in codon usage, and leader-sequence optimizations — all of which improve the immune potency of DNA vaccines.

  • New formulations, including lipids and polymers, and new delivery devices, including the gene gun, skin-delivery devices and, most recently, electroporation technology, seem to be promising in preclinical models and will be followed closely in the clinic.

  • Strong molecular adjuvants that are included in plasmid formulations seem to be important and are particularly well suited for further improving immune potency of DNA vaccines and for controlling the phenotype of the induced immune response.

  • In the past 3 years, four DNA vaccine or immune therapy products have been licensed in the veterinary arena for diverse species, including salmon, pigs, dogs and horses. These products are the first validation of the commercial viability of the DNA vaccine platform and illustrate strong progress in this area.

  • Progress in the DNA platform will continue to be an exciting and highly productive adventure, illustrating the best in academic and translational science and cooperation between industry, the regulatory authorities, funding agencies and academicians.

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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Figure 1: DNA vaccines: optimization strategies to enhance immunogenicity.

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Acknowledgements

We would like to thank members of the Weiner laboratory for helpful discussions, including M.P. Morrow, D. Hokey, D. Laddy and K. Schoenly. We apologize for any important work that was not cited in this article owing to space limitations. The work in D.B.W.'s laboratory is supported in part by funding from the National Institutes of Health.

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Authors and Affiliations

  1. Division of Infectious Diseases and HIV Medicine, The Department of Medicine, Drexel University College of Medicine, 245 North 15th Street, Philadelphia, 19102, Pennsylvania, USA

    Michele A. Kutzler

  2. The Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, 422 Curie Boulevard, Philadelphia, 19104, Pennsylvania, USA

    David B. Weiner

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  1. Michele A. Kutzler
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  2. David B. Weiner
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Correspondence to David B. Weiner.

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Competing interests

The laboratory of D.B.W. has grant funding and collaborations or consulting, including serving on scientific review committees for commercial entities, and in the interest of disclosure therefore notes potential conflicts associated with this work with Wyeth, VGX Pharmaceuticals, Bristol Myers Squibb, Virxsys, Ichor, Merck, Althea, Aldeveron and Inovio, and possibly others. M.A.K. has no competing interests.

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Vical

Glossary

Formulation

A mixture of one or more active ingredients is made safe and easy to store, transport, dilute or apply through the presence of other materials (for example, vehicles or solvents).

Cytotoxic T lymphocyte

(CTL. Also known as TC, T-killer cell or killer T cell). Belongs to a sub-group of T lymphocytes that are capable of inducing the death of infected somatic or tumour cells. They target and kill cells that are infected with other pathogens or that are otherwise damaged or dysfunctional.

Adjuvant

An agent that can stimulate the immune system and increase the response to a vaccine, without having any specific antigenic immune response.

Codon optimization

The preference that different organisms show for one of the several codons that encode a particular amino acid. Translationally optimal codons are those that are recognized by abundant tRNAs. Within a phylogenetic group, the frequency of particular codons in a gene is highly correlated with higher translation rates and accuracy.

Subcutaneum

The layer of tissue that lies just under the surface of the skin.

Antigen presenting cell

(APC). Specialized cell that can prime naive T cells through the expression of MHC class I molecules (which are expressed by most cells and can prime CD8+ cytotoxic T cells) as well as MHC class II molecules (which prime CD4+ T helper cells).

Vector interference

The observation that re-administration of the same bacterial or viral vector leads to a reduction in its potency. This occurs because the host's immune response develops neutralizing antibody responses against the vector when it is first administered. DNA does not contain protein targets so there is no vector interference or loss of potency following DNA re-administration.

Electroporation

A physical process that exposes the target tissue to a brief electric-field pulse in order to induce temporary and reversible pores in the cell membrane. During the period of membrane destabilization, molecules such as plasmids can gain intracellular access.

Adventitial agents

Unknown pathogens that are present in the cell lines that are used to produce vaccines and that can become part of the final vaccine preparation. SV40 was discovered this way, as a contaminant of the polioviral vaccine. As DNA vaccines are not produced in mammalian cell culture they can not contain these agents.

Cynomolgus monkey

(Macaca fascicularis). A primarily arboreal macaque that is native to Southeast Asia. It is also called the long-tailed macaque.

Kozak consensus sequence

A specific sequence that occurs on eukaryotic mRNA. This sequence is recognized and required by the ribosome as the translational start site.

Cross-neutralizing antibody

An antibody that recognizes a wide range of antigenic epitopes.

Consensus immunogens

Immunogens that are designed using computer analysis and then coded in DNA vaccines. They are synthesized so that the genes represent the most common amino acid at any position in a sequence, based on a population of viral isolate sequences.

Phage display

A method that uses bacteriophage for high-throughput screening of protein interactions with other proteins, DNA or peptides.

Liposome

Made up of bilayered membranes consisting of polar and non-polar portions of phospholipids that form multilayered shells containing a charged DNA-binding region.

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Kutzler, M., Weiner, D. DNA vaccines: ready for prime time?. Nat Rev Genet 9, 776–788 (2008). https://doi.org/10.1038/nrg2432

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