The current bioterrorism threat has refocused our nation on the issue of our population's susceptibility to a smallpox attack. As a precaution, deployment of dilution of the current stock of vaccine and deployment of a tissue culture version of the VACV vaccine have been requisitioned. This vaccine and likely the new stocks carried a risk of Significant Adverse Events of 1 per 10,000 vaccinated individuals. However, that vaccine was last used in a very different environment. The high-risk groups for AE's include the elderly, the very young, immunocompromised individuals and others. The percentage and absolute numbers of the US population that falls within these categories has risen dramatically in the past 30 years. The greater than 750,000 persons living in the US that are HIV-positive is one clear example. This suggests that the AE risk of the VACV may be unacceptable and can only be deployed as a last resort. However, the option of abandoning this approach and developing new approaches leaves us at risk for a possibly unknown period of time. The hypothesis to be tested in this application is that there is a third option, to develop a strategy that uses the current vaccine yet limits its pathogenesis while improving its potency. It is our hypothesis that priming with enhanced expressing plasmid vaccines that induce nonneutralizing cellular immune responses will prime for successful and even enhanced boosting with the current vaccine, yet limit its associated pathogenesis. This application will use quantitative T cell assays including Elispot and ICC and tetramer analysis, and novel human HLA+DR positive transgenic mice that we have developed to pursue the three specific aims. Novel cellular reagents including MHC class I tetramers will be developed that will have significant value in following VACV challenge in humans as they may be useful as cellular surrogates for the current site reaction take. Together these studies will establish if this simple and novel approach can bridge the current situation and produce a safer more effective smallpox vaccine. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AI054988-03
Application #
6887329
Study Section
Special Emphasis Panel (ZAI1-ALR-M (J1))
Program Officer
Challberg, Mark D
Project Start
2003-05-15
Project End
2008-04-30
Budget Start
2005-05-01
Budget End
2006-04-30
Support Year
3
Fiscal Year
2005
Total Cost
$492,742
Indirect Cost
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Otero, Miguel; Calarota, Sandra A; Dai, Anlan et al. (2006) Efficacy of novel plasmid DNA encoding vaccinia antigens in improving current smallpox vaccination strategy. Vaccine 24:4461-70
Agadjanyan, Michael G; Chattergoon, Michael A; Holterman, Mark J et al. (2003) Costimulatory molecule immune enhancement in a plasmid vaccine model is regulated in part through the Ig constant-like domain of CD80/86. J Immunol 171:4311-9