Report Summary

Toxicological Safety Evaluation of DNA Plasmid Vaccines against HIV-1, Ebola, Severe Acute Respiratory Syndrome, or West Nile Virus Is Similar Despite Differing Plasmid Backbones or Gene-Inserts

Study Summary

Overall Study Design 
The Vaccine Research Center has developed a number of vaccine candidates for different diseasesinfectious agents HIV-
1 Severe Acute Respiratory Syndrome virus West Nile virus and Ebola virus plus a plasmid cytokine adjuvantIL-2Ig 
based on a DNA plasmid vaccine platform To support the clinical development of each of these vaccine candidates 
preclinical 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 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 time points This observation also correlated with the biodistribution data reported in the 
companion article Sheets et al 2006 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 Food and 
Drug Administration 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 ie 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 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 
Before regulatory agencies approve initiation of human clinical trials of novel vaccines a basis for their safety must be 
established Generally this is accomplished by the conduct of a general toxicological screening protocol to identify 
potential toxicological signals or target organs to guide clinical safety monitoring the purpose of such a study is to identify 
potential toxicological signals or target organs to guide clinical safety monitoring The purpose of such a study is to identify 
both intrinsic toxicity of the product as well as immunotoxicity arising from the host immune response to the vaccine Rabbits 
are often used for such screening protocols because while they may not be the perfect animal model for all products they 
represent a species large enough to receive a full human dose of vaccine This is important since the 
immunogenicitypharmaceutical effect of vaccines does not scale directly on body weight or body surface area as may be 
the case for most drugs which disseminate through the blood to other parts of the body Vaccines act at the local site of 
injection if delivered parenterally to induce an immune response that traffics systemically Thus delivery of a full human 
dose to the animal model is deemed the most suitable means of addressing potential human toxicities 
Concern about the potential for vaccines to induce immunotoxicity has been a regulatory concern for decades The 
seriousness of immunotoxicity is perhaps most strikingly illustrated by the occurrence of rheumatic heart disease which 
develops as a consequence of the host immune response to Group A streptococcus GAS infections 
DNA vaccines are a novel product class with limited though ever-increasing clinical experience Preclinical testing 

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