Abstract

The Animal Models Core, will serve three major purposes within the SARS Coronavirus Vaccine Development Program. 1) The core will develop standardized assays and reagents for evaluating the immune responses induced by wild-type SARS-CoV, as well as the panel of live attenuated, inactivated, and replicon vector delivered SARS-CoV vaccine candidates developed in projects 1-4 and Core C. 2) The core will evaluate the recombinant mutant SARS-CoV developed in this program project for effects on in vivo replication in a recently developed mouse model, and in vivo replication and pathogenesis in a ferret model of SARS-CoV-induced disease. These studies will provide important insights in to the role of specific viral genes in the pathogenesis of SARS-CoV respiratory infection. It is also expected that studies within this core will identify attenuated SARS-CoV mutants that whose safety profiles in the ferret will make them good candidates as live attenuated vaccines. 3) The core will perform a head to head comparison of live attenuated SARS-CoV vaccines that prove safe in the ferret model, as well as inactivated and replicon delivered vaccines. These studies will involve an in depth and stepwise assessment of each vaccine's ability to safely induce SARS-CoV specific immune responses and to protect from SARS-CoV challenge in the mouse and ferret models. The ultimate goal of this core, as well as the program project as a whole, is to develop candidate live attenuated, inactivated, or vector delivered vaccines that will safely and effectively protect against SARS-CoV infection. Vaccines that safely induce protective immunity against SARS-CoV challenge in the mouse and ferret models, will be considered to be good candidates for additional safety and efficacy testing in non-human primates.
Specific Aims :
Aim 1. Immune response assay development and optimization Aim 2. Evaluation of recombinant SARS-CoV for replication and disease phenotypes in small animal models.
Aim 3. Evaluation of live attenuated, inactivated, VLP, and recombinant vector-based SARS-CoV vaccines for induction of protective immune responses.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI059443-05
Application #
7760882
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2009-02-01
Budget End
2010-01-31
Support Year
5
Fiscal Year
2009
Total Cost
$316,112
Indirect Cost

  Institution

Name
University of North Carolina Chapel Hill
Department
Type
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599

  Publications

Gonzalez, P N; Pavlicev, M; Mitteroecker, P et al. (2016) Genetic structure of phenotypic robustness in the collaborative cross mouse diallel panel. J Evol Biol 29:1737-51
Sheahan, Timothy; Whitmore, Alan; Long, Kristin et al. (2011) Successful vaccination strategies that protect aged mice from lethal challenge from influenza virus and heterologous severe acute respiratory syndrome coronavirus. J Virol 85:217-30
Brooke, Christopher B; Deming, Damon J; Whitmore, Alan C et al. (2010) T cells facilitate recovery from Venezuelan equine encephalitis virus-induced encephalomyelitis in the absence of antibody. J Virol 84:4556-68
Li, Kelvin; Venter, Eli; Yooseph, Shibu et al. (2010) ANDES: Statistical tools for the ANalyses of DEep Sequencing. BMC Res Notes 3:199
Rockx, Barry; Donaldson, Eric; Frieman, Matthew et al. (2010) Escape from human monoclonal antibody neutralization affects in vitro and in vivo fitness of severe acute respiratory syndrome coronavirus. J Infect Dis 201:946-55
Frieman, Matthew B; Chen, Jun; Morrison, Thomas E et al. (2010) SARS-CoV pathogenesis is regulated by a STAT1 dependent but a type I, II and III interferon receptor independent mechanism. PLoS Pathog 6:e1000849
Zornetzer, Gregory A; Frieman, Matthew B; Rosenzweig, Elizabeth et al. (2010) Transcriptomic analysis reveals a mechanism for a prefibrotic phenotype in STAT1 knockout mice during severe acute respiratory syndrome coronavirus infection. J Virol 84:11297-309
Eckerle, Lance D; Becker, Michelle M; Halpin, Rebecca A et al. (2010) Infidelity of SARS-CoV Nsp14-exonuclease mutant virus replication is revealed by complete genome sequencing. PLoS Pathog 6:e1000896
Frieman, Matthew; Ratia, Kiira; Johnston, Robert E et al. (2009) Severe acute respiratory syndrome coronavirus papain-like protease ubiquitin-like domain and catalytic domain regulate antagonism of IRF3 and NF-kappaB signaling. J Virol 83:6689-705
Rockx, Barry; Baas, Tracey; Zornetzer, Gregory A et al. (2009) Early upregulation of acute respiratory distress syndrome-associated cytokines promotes lethal disease in an aged-mouse model of severe acute respiratory syndrome coronavirus infection. J Virol 83:7062-74

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