The complement (C1) system is comprised of critical host innate immune mediators that help control invading organisms. Activation of C' is also a major link between the innate and adaptive immune systems and serves to augment both humoral and cellular immune responses. Orthopoxviruses encode secreted proteins that inhibit host C'-activation and block C'-mediated virus neutralization and inflammation. Thus, the poxvirus genes that encode complement control proteins (CCP) are ideal candidates with which to further attenuate smallpox vaccines. Importantly, it is not known whether manipulating these CCPs could also augment C'-enhanced adaptive immunity to the virus. We hypothesize that the vaccinia complement control protein (VCP) is a virulence factor with both a central role in protecting the virus from innate immunity and an immunoregulatory role that down regulates the magnitude, duration, and quality of antigen-specific T and B cell responses. We further hypothesize that by altering the VCP gene we can both further attenuate the virus to make a safer vaccine as well as enhance adaptive immune responses that would confer superior protection. To develop candidate smallpox vaccines that manipulate the function of VCP, we will: 1. Define the in vitro replication and in vivo pathogenicity of vaccinia virus mutants in which we selectively modify the VCP gene to manipulate its function. 2. Define the humoral and cellular immune responses to smallpox vaccines with modified VCP functions. 3. Define the protection conferred by vaccinations with viruses containing modified VCP in the context of both orthopoxvirus and heterologous challenge models. We believe that VCP is a promising target for novel vaccine strategies that has the potential to enhance both the safety and immunogenicity of next generation smallpox vaccines ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AI066333-03
Application #
7247181
Study Section
Special Emphasis Panel (ZAI1-TH-M (M3))
Program Officer
Challberg, Mark D
Project Start
2005-07-05
Project End
2010-06-30
Budget Start
2007-07-01
Budget End
2008-06-30
Support Year
3
Fiscal Year
2007
Total Cost
$311,712
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
Hudson, Paul N; Self, Joshua; Weiss, Sonja et al. (2012) Elucidating the role of the complement control protein in monkeypox pathogenicity. PLoS One 7:e35086
Xiao, Yuhong; Isaacs, Stuart N (2012) Enzyme-linked immunosorbent assay (ELISA) and blocking with bovine serum albumin (BSA)--not all BSAs are alike. J Immunol Methods 384:148-51
Wang, Liang-Chuan S; Lynn, Rachel C; Cheng, Guanjun et al. (2012) Treating tumors with a vaccinia virus expressing IFN? illustrates the complex relationships between oncolytic ability and immunogenicity. Mol Ther 20:736-48
Isaacs, Stuart N (2012) Working safely with vaccinia virus: laboratory technique and review of published cases of accidental laboratory infections. Methods Mol Biol 890:1-22
Isaacs, Stuart N (2011) A stimulating way to improve T cell responses to poxvirus-vectored vaccines. J Clin Invest 121:19-21
Girgis, Natasha M; Dehaven, Brian C; Xiao, Yuhong et al. (2011) The Vaccinia virus complement control protein modulates adaptive immune responses during infection. J Virol 85:2547-56
Dehaven, Brian C; Gupta, Kushol; Isaacs, Stuart N (2011) The vaccinia virus A56 protein: a multifunctional transmembrane glycoprotein that anchors two secreted viral proteins. J Gen Virol 92:1971-80
Xiao, Yuhong; Isaacs, Stuart N (2010) Therapeutic Vaccines and Antibodies for Treatment of Orthopoxvirus Infections. Viruses 2:2381-2403
DeHaven, Brian C; Girgis, Natasha M; Xiao, Yuhong et al. (2010) Poxvirus complement control proteins are expressed on the cell surface through an intermolecular disulfide bridge with the viral A56 protein. J Virol 84:11245-54
Mustafa, Waleed; Maciag, Paulo Cesar; Pan, Zhen-kun et al. (2009) Listeria monocytogenes delivery of HPV-16 major capsid protein L1 induces systemic and mucosal cell-mediated CD4+ and CD8+ T-cell responses after oral immunization. Viral Immunol 22:195-204

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