ToxSci Advance Access published online on March 28, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfj170
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1 NIH/NIAID/Vaccine Research Center, Vaccine Production Program, Room 5145, 6700B Rockledge Dr. MSC-7628, Bethesda, MD 20892-7628, For Fed Ex. please change Zip to 20817-7628, (301)402-3684 (fax)
* To whom correspondence should be addressed. 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 an 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 were performed to screen for potential toxicities (intrinsic and immunotoxicities). All treatment-related toxicities identified in these repeated dose toxicology studies have been confined primarily to the sites of injection and seem to be the result of both the delivery method (as they are seen in both control and treated animals) and to the intended immune response to the vaccine (as they occur with greater frequency and severity in treated animals). Reactogenicity at the site of injection is generally seen to be reversible as the frequency and severity diminished between doses and between the immediate and recovery termination timepoints. This observation also correlated with the biodistribution data reported in the companion article, in which DNA plasmid vaccine was shown to remain at the site of injection, rather than biodistributing widely, and to clear over time. The results of these safety studies have been submitted to the FDA to support the safety of initiating clinical studies with these and related DNA plasmid vaccines. Thus far, standard repeated dose toxicology studies have not identified any target organs for toxicity (other than the injection site) for our DNA plasmid vaccines at doses up to 8 mg per immunization, regardless of disease indication (i.e., expressed gene-insert) and despite differences (strengths) in the promoters used to drive this expression. As clinical data accumulate with these products, it will be possible to retrospectively compare the safety profiles of the products in the clinic to the results of the repeated dose toxicology studies, in order to determine the utility of such toxicology studies for signaling potential immunotoxicities or intrinsic toxicities from DNA vaccines. These data build on the biodistribution 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.
Received November 23, 2005
Accepted March 17, 2006
Safety Evaluation
Toxicological Safety Evaluation of DNA Plasmid Vaccines against Human Immunodeficiency Virus-1 (HIV-1), Ebola, Severe Acute Respiratory Syndrome (SARS), or West Nile Virus (WNV) is Similar Despite Differing Plasmid Backbones or Gene Inserts
Rebecca L. Sheets 1 *,
Judith Stein 2,
T. Scott Manetz 3,
Charla Andrews 4,
Robert Bailer 5,
John Rathmann 6,
and
Phillip L. Gomez III 7
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 Vaccine Production Program/Regulatory Affairs, Vaccine Research Center/NIAID/NIH, Building 40, Room 5508, MSC 3011, 40 Convent Drive, Bethesda, MD 20892-3011, 301-480-2788 (fax)
5 Immunology Core Laboratory Section, Vaccine Research Center-NIH/NIAID, 40 Convent Drive, MSC 3022, Building 40, Room 3508, Bethesda, MD 20892, Fax: 301-480-2565
6 Immunology Core Laboratory Section, Vaccine Research Center-NIH/NIAID, 40 Convent Drive, MSC 3022, Building 40, Room 3508, Bethesda, MD 20892
7 Vaccine Production, Vaccine Research Center, NIAID, NIH, Bldg. 40, Room 5502, MSC-3011, 40 Convent Drive, Bethesda, MD 20892-3011, (301) 480-2788 (FAX)
Rebecca L. Sheets, E-mail: rsheets{at}niaid.nih.gov
Abstract 
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