ToxSci Advance Access originally published online on March 28, 2006
Toxicological Sciences 2006 91(2):610-619; doi:10.1093/toxsci/kfj169
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Published by Oxford University Press 2006.
Biodistribution of DNA Plasmid Vaccines against HIV-1, Ebola, Severe Acute Respiratory Syndrome, or West Nile Virus Is Similar, without Integration, despite Differing Plasmid Backbones or Gene Inserts
* U.S. Public Health Service, Vaccine Production Program, NIH/NIAID/Vaccine Research Center, Bethesda, Maryland 20892-7628; Vaccine Research Center/NIAID/NIH, Bethesda, Maryland 20892; Toxicology Dept., Gene Logic Inc., Gaithersburg, Maryland 20879; Analytical Services, Althea Technologies, Inc., San Diego, California 92121; ¶ NIH/NIAID, Bethesda, Maryland 20892; || Vaccine Production Program/Regulatory Affairs, Vaccine Research Center/NIAID/NIH, Bethesda, Maryland 20892-3011; and ||| Vaccine Production, Vaccine Research Center, NIAID, NIH, Bethesda, Maryland 20892-3011
Received November 23, 2005; accepted March 17, 2006
The Vaccine Research Center has developed a number of vaccine candidates for different diseases/infectious agents (HIV-1, Severe Acute Respiratory Syndrome virus, West Nile virus, 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, preclinical 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 postinoculation), already all but on the order of 104–106 molecules per microgram of DNA extracted from tissue have been cleared at the injection site. Over the course of 2 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 i.m. by Biojector 2000 or by needle and syringe. These data build on the repeated-dose toxicology studies performed (see companion article, Sheets et al., 2006) to demonstrate the safety and suitability for investigational human use of DNA plasmid vaccine candidates for a variety of infectious disease prevention indications.
Key Words: DNA vaccines; HIV/AIDS; SARS; WNV; Ebola; DNA vaccine biodistribution; DNA vaccine integration; plasmid vaccines.
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