Abstract

Replication competent vaccinia virus (W), the current vaccine for smallpox, can cause severe complications after vaccination, especially in immune suppressed individuals. We are seeking to develop attenuated strains of W that are replication competent, and thus will induce a strong immune response, without the complications associated with vaccination with the current vaccines. Thus, the Aim of this proposal is to further develop existing strains of vaccinia virus that contain mutations in a key innate immune evasion gene, the E3L IFN-resistance gene, as safe effective alternatives to the current and proposed smallpox vaccines. We have deleted the E3L gene from a tissue culture adapted variant of the NYCBH strain of W, ACAM2000. The relative immunogenicity, adjuvancy and safety of ACAM2000delE3L will be compared with that of ACAM2000 and Dryvax in mice (immunogenicity and safety). Efficacy will be tested against ectromelia, rabbitpox and monkeypox challenges in mice, rabbits and macaques, respectively, compared to Dryvax. The intent is to use this data to satisfy the FDA Animal Efficacy Rule, and pave the way for Phase l/ll Clinical Trials in healthy human volunteers. ? ?

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AI066326-02
Application #
7091654
Study Section
Special Emphasis Panel (ZAI1-TH-M (M3))
Program Officer
Challberg, Mark D
Project Start
2005-07-10
Project End
2009-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
2
Fiscal Year
2006
Total Cost
$418,119
Indirect Cost

  Institution

Name
Arizona State University-Tempe Campus
Department
Other Health Professions
Type
Organized Research Units
DUNS #
943360412
City
Tempe
State
AZ
Country
United States
Zip Code
85287

  Publications

Huynh, Trung P; Jancovich, James K; Tripuraneni, Latha et al. (2017) Characterization of a PKR inhibitor from the pathogenic ranavirus, Ambystoma tigrinum virus, using a heterologous vaccinia virus system. Virology 511:290-299
White, Stacy D; Jacobs, Bertram L (2012) The amino terminus of the vaccinia virus E3 protein is necessary to inhibit the interferon response. J Virol 86:5895-904
Denzler, Karen L; Babas, Tahar; Rippeon, Amy et al. (2011) Attenuated NYCBH vaccinia virus deleted for the E3L gene confers partial protection against lethal monkeypox virus disease in cynomolgus macaques. Vaccine 29:9684-90
Denzler, Karen L; Schriewer, Jill; Parker, Scott et al. (2011) The attenuated NYCBH vaccinia virus deleted for the immune evasion gene, E3L, completely protects mice against heterologous challenge with ectromelia virus. Vaccine 29:9691-6
Denzler, Karen L; Rice, Amanda D; MacNeill, Amy L et al. (2011) The NYCBH vaccinia virus deleted for the innate immune evasion gene, E3L, protects rabbits against lethal challenge by rabbitpox virus. Vaccine 29:7659-69
Jacobs, Bertram L; Langland, Jeffrey O; Kibler, Karen V et al. (2009) Vaccinia virus vaccines: past, present and future. Antiviral Res 84:1-13
Zhang, Ping; Langland, Jeffrey O; Jacobs, Bertram L et al. (2009) Protein kinase PKR-dependent activation of mitogen-activated protein kinases occurs through mitochondrial adapter IPS-1 and is antagonized by vaccinia virus E3L. J Virol 83:5718-25
Jentarra, Garilyn M; Heck, Michael C; Youn, Jin Won et al. (2008) Vaccinia viruses with mutations in the E3L gene as potential replication-competent, attenuated vaccines: scarification vaccination. Vaccine 26:2860-72
Vijaysri, Sangeetha; Jentarra, Garilyn; Heck, Michael C et al. (2008) Vaccinia viruses with mutations in the E3L gene as potential replication-competent, attenuated vaccines: intra-nasal vaccination. Vaccine 26:664-76
Zhang, Ping; Jacobs, Bertram L; Samuel, Charles E (2008) Loss of protein kinase PKR expression in human HeLa cells complements the vaccinia virus E3L deletion mutant phenotype by restoration of viral protein synthesis. J Virol 82:840-8

Showing the most recent 10 out of 11 publications