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

Rebecca L. Sheets, Judith Stein, T. Scott Manetz, Chris Duffy, Martha Nason, Charla Andrews, Wing Pui Kong, Gary J. Nabel, Phillip L. Gomez

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)610-619
Number of pages10
JournalToxicological Sciences
Volume91
Issue number2
DOIs
StatePublished - Jun 2006
Externally publishedYes

Fingerprint

Severe Acute Respiratory Syndrome
West Nile virus
DNA Vaccines
Viruses
HIV-1
Plasmids
Genes
Vaccines
Injections
Communicable Diseases
Muscle
Ebolavirus
SARS Virus
Cytokines
Rabbits
Syringes
Muscles
Molecules
Needles
Toxicology

Keywords

  • DNA vaccine biodistribution
  • DNA vaccine integration
  • DNA vaccines
  • Ebola
  • HIV/AIDS
  • Plasmid vaccines
  • SARS
  • WNV

ASJC Scopus subject areas

  • Toxicology

Cite this

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. / Sheets, Rebecca L.; Stein, Judith; Manetz, T. Scott; Duffy, Chris; Nason, Martha; Andrews, Charla; Kong, Wing Pui; Nabel, Gary J.; Gomez, Phillip L.

In: Toxicological Sciences, Vol. 91, No. 2, 06.2006, p. 610-619.

Research output: Contribution to journalArticle

Sheets, Rebecca L. ; Stein, Judith ; Manetz, T. Scott ; Duffy, Chris ; Nason, Martha ; Andrews, Charla ; Kong, Wing Pui ; Nabel, Gary J. ; Gomez, Phillip L. / 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. In: Toxicological Sciences. 2006 ; Vol. 91, No. 2. pp. 610-619.
@article{613b7194ad124b69bb43e64aa57d6612,
title = "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",
abstract = "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.",
keywords = "DNA vaccine biodistribution, DNA vaccine integration, DNA vaccines, Ebola, HIV/AIDS, Plasmid vaccines, SARS, WNV",
author = "Sheets, {Rebecca L.} and Judith Stein and Manetz, {T. Scott} and Chris Duffy and Martha Nason and Charla Andrews and Kong, {Wing Pui} and Nabel, {Gary J.} and Gomez, {Phillip L.}",
year = "2006",
month = "6",
doi = "10.1093/toxsci/kfj169",
language = "English (US)",
volume = "91",
pages = "610--619",
journal = "Toxicological Sciences",
issn = "1096-6080",
publisher = "Oxford University Press",
number = "2",

}

TY - JOUR

T1 - 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

AU - Sheets, Rebecca L.

AU - Stein, Judith

AU - Manetz, T. Scott

AU - Duffy, Chris

AU - Nason, Martha

AU - Andrews, Charla

AU - Kong, Wing Pui

AU - Nabel, Gary J.

AU - Gomez, Phillip L.

PY - 2006/6

Y1 - 2006/6

N2 - 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.

AB - 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.

KW - DNA vaccine biodistribution

KW - DNA vaccine integration

KW - DNA vaccines

KW - Ebola

KW - HIV/AIDS

KW - Plasmid vaccines

KW - SARS

KW - WNV

UR - http://www.scopus.com/inward/record.url?scp=33744790917&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33744790917&partnerID=8YFLogxK

U2 - 10.1093/toxsci/kfj169

DO - 10.1093/toxsci/kfj169

M3 - Article

C2 - 16569729

AN - SCOPUS:33744790917

VL - 91

SP - 610

EP - 619

JO - Toxicological Sciences

JF - Toxicological Sciences

SN - 1096-6080

IS - 2

ER -