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ToxSci Advance Access published online on March 28, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfj169
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Published by Oxford University Press 2006.
Received November 23, 2005
Accepted March 17, 2006

Safety Evaluation

Biodistribution of DNA Plasmid Vaccines against Human Immunodeficiency Virus-1 (HIV-1), Ebola, Severe Acute Respiratory Syndrome (SARS), or West Nile Virus (WNV) is Similar, Without Integration, Despite Differing Plasmid Backbones or Gene Inserts

Rebecca L. Sheets 1 *, Judith Stein 2, T. Scott Manetz 3, Chris Duffy 4, Martha Nason 5, Charla Andrews 6, Wing-Pui Kong 7, Gary J. Nabel 8, and Phillip L. Gomez III 9

1 NIH/NIAID/Vaccine Research Center, Vaccine Production Program, Room 5145, 6700B Rockledge Dr. MSC-7628, Bethesda, MD 20892-7628, (301)402-3684 (fax)
2 Vaccine Research Center/NIAID/NIH, Technology Transfer and Development, Henry M. Jackson Foundation, Fax: 734 764-3596
3 Immunotoxicology Gene Logic Inc., 610 Professional Drive, Gaithersburg, MD 20879, (301)987-1711-fax
4 Analytical Services, Althea Technologies, Inc., 11040 Roselle St., San Diego, CA 92121, fax. 858-882-0133
5 NIH/NIAID, 6700A Rockledge Dr. Rm. 5231, Bethesda, MD 20892, 301-451-5134
6 Vaccine Production Program/Regulatory Affairs, Vaccine Research Center/NIAID/NIH, Building 40, Room 5508, MSC 3011, 40 Convent Drive, Bethesda, MD 20892-3011, 301-594-8488 (work), 301-480-2788 (fax)
7 NIH/NIAID/Vaccine Research Center, 40 Convent Drive Rm. 4608, Bethesda, MD 20892, 301-594-8237
8 Vaccine Research Center, NIH/NIAID, 40 Convent Drive Rm. 4502, Bethesda, MD 20892, 301-496-1852
9 Vaccine Production, Vaccine Research Center, NIAID, NIH, Bldg. 40, Room 5502, MSC-3011, 40 Convent Drive, Bethesda, MD 20892-3011, (301) 480-2788 (FAX)

* To whom correspondence should be addressed.
Rebecca L. Sheets, E-mail: rsheets{at}niaid.nih.gov


  Abstract

The Vaccine Research Center has developed a number of vaccine candidates for different diseases/infectious agents (HIV-1, SARS virus, WNV, and Ebola virus, plus a plasmid cytokine adjuvant - IL-2/Ig) based on a DNA plasmid vaccine platform. To support the clinical development of each of these vaccine candidates, pre-clinical studies have been performed in mice or rabbits to determine where in the body these plasmid vaccines would biodistribute and how rapidly they would clear. In the course of these studies, it has been observed that regardless of the gene-insert (expressing the vaccine immunogen or cytokine adjuvant) and regardless of the promoter used to drive expression of the gene-insert in the plasmid backbone, the plasmid vaccines do not biodistribute widely and remain essentially in the site of injection, in the muscle and overlying subcutis. Even though ~1014 molecules are inoculated in the studies in rabbits, by day 8 or 9 (~1 week post-inoculation), already all but on the order of 104 to 106 molecules per µg of DNA extracted from tissue has been cleared at the injection site. Over the course of two months, the plasmid clears from the site of injection with only a small percentage of animals (generally 10-20%) retaining a small number of copies (generally around 100 copies) in the muscle at the injection site. This pattern of biodistribution (confined to the injection site) and clearance (within 2 months) is consistent regardless of differences in the promoter in the plasmid backbone or differences in the gene-insert being expressed by the plasmid vaccine. In addition, integration has not been observed with plasmid vaccine candidates inoculated intramuscularly by Biojector 2000® or by needle- and-syringe. These data build on the repeated dose toxicology studies performed (see companion article) to demonstrate the safety and suitability for investigational human use of DNA plasmid vaccine candidates for a variety of infectious disease prevention indications.

Keywords: DNA vaccines; HIV/AIDS; SARS; WNV; Ebola; DNA vaccine biodistribution; DNA vaccine integration; plasmid vaccines.
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