The major objectives of this Co-operative Research Program will be to: (1) develop a vaccine candidate(s) to protect against inhalational tularemia (caused by Francisella tularensis); (2) to develop a polyconal antibody library to be used for passive immunization to ameliorate or prevent acute illness from F. tularensis acquired by the inhalational route and (3) to develop diagnostic systems to detect F. tularensis in clinical specimens and in the environment using immunochemical and/or gene amplification methods. In Project 1, we will prepare and use as vaccine candidates in experimental systems, F. tularensis lipopolysaccharide derived O-polysaccharide and capsular polysaccharides. We will use conjugates and clinically relevant adjuvant and delivery systems to recruit T cell help to enhance immune responses. We will also create peptide surrogates (called mimics) of the two saccharide prototypes and use these for immunization. Mice will be immunized to assess vaccine efficacy against aerosol challenge with F. tularensis. In Project 2, we will design polyclonal antibody expression libraries against F. tularensis and examine the efficacy of passive administration in preventing and treating experimentally induced inhalational tularemia. We will use widely directed polyclonal antibodies to determine overall efficacy, use libraries depleted of putative subversive (blocking) antibodies and generate monospecific polyclonals directed against O-polysaccharides to passively immunize mice and assess protection from aerosol challenge with F. tularensis. In Project 3, we will develop three diagnostic systems, using gene amplification and immunochemical detection, to detect F. tularensis in clinical and environmental specimens. A transcription mediated amplification (TMA) assay will be developed to detect F. tularensis in respiratory secretions and an immunochemical test to detect Francisella antigens in respiratory secretions and urine and for monitoring environmental air samples.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI056543-03
Application #
6857080
Study Section
Special Emphasis Panel (ZAI1-ALR-M (M4))
Program Officer
Schaefer, Michael R
Project Start
2003-09-15
Project End
2008-02-29
Budget Start
2005-03-01
Budget End
2006-02-28
Support Year
3
Fiscal Year
2005
Total Cost
$2,310,008
Indirect Cost
Name
Boston Medical Center
Department
Type
DUNS #
005492160
City
Boston
State
MA
Country
United States
Zip Code
02118
Roche, Marly I; Lu, Zhaohua; Hui, Julia H et al. (2011) Characterization of monoclonal antibodies to terminal and internal O-antigen epitopes of Francisella tularensis lipopolysaccharide. Hybridoma (Larchmt) 30:19-28
Chiavolini, Damiana; Rangel-Moreno, Javier; Berg, Gretchen et al. (2010) Bronchus-associated lymphoid tissue (BALT) and survival in a vaccine mouse model of tularemia. PLoS One 5:e11156
Chiavolini, Damiana; Weir, Susan; Murphy, John R et al. (2008) Neisseria meningitidis PorB, a Toll-like receptor 2 ligand, improves the capacity of Francisella tularensis lipopolysaccharide to protect mice against experimental tularemia. Clin Vaccine Immunol 15:1322-9
Chiavolini, Damiana; Alroy, Joseph; King, Carol A et al. (2008) Identification of immunologic and pathologic parameters of death versus survival in respiratory tularemia. Infect Immun 76:486-96
Lu, Zhaohua; Roche, Marly I; Hui, Julia H et al. (2007) Generation and characterization of hybridoma antibodies for immunotherapy of tularemia. Immunol Lett 112:92-103