The recent, intentional dissemination of Bacillus anthracis caused significant morbidity and mortality, as well as widespread and costly disruption of essential public services. The resulting re-evaluation of current methods for the prevention and treatment of anthrax has revealed significant gaps in our knowledge of the basic immunobiology of this disease, and highlighted the need to develop methodologies for establishing vaccine efficacy in the absence of clinical trials. The research described in this proposal will define the molecular and structural characteristics of the protective antibody response elicited by the currently licensed human anthrax vaccine. Methods of repertoire cloning recently developed in our laboratory will be used to establish at the molecular level the structural diversity, variable gene usage, and somatic maturational history of the human antibody repertoire specific for the protective antigen (PA) of B. anthracis. The extent to which different individuals utilize the same immunoglobulin variable gene products to bind specific epitopes on the antigen will be determined. Through sequence analysis, the degree to which responding antibody clones have undergone somatic maturation will be ascertained. Clonally derived PA-specific binding domains will be expressed in vitro, the subset capable of blocking PA functional activity identified, and affinity and valence requirements for functionality established. Cloned antibody binding domains will be used to define the PA-associated antigenic epitopes recognized by the human immune response, and to pinpoint those PA-associated epitopes that elicit neutralizing antibodies. Our findings will be crucial for the rational design of PA subunit vaccines, and will aid in establishing in vitro correlates of protective immunity to B. anthracis infection. In addition, the antibodies isolated will constitute a panel of fully human monoclonal binding domains with potential for therapeutic use as passive immunogens. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI057932-01A1
Application #
6820498
Study Section
Special Emphasis Panel (ZRG1-SSS-F (02))
Program Officer
Baker, Phillip J
Project Start
2004-06-01
Project End
2009-05-31
Budget Start
2004-06-01
Budget End
2005-05-31
Support Year
1
Fiscal Year
2004
Total Cost
$400,250
Indirect Cost
Name
Children's Hospital & Res Ctr at Oakland
Department
Type
DUNS #
076536184
City
Oakland
State
CA
Country
United States
Zip Code
94609
Giuntini, Serena; Beernink, Peter T; Reason, Donald C et al. (2012) Monoclonal antibodies to meningococcal factor H binding protein with overlapping epitopes and discordant functional activity. PLoS One 7:e34272
Giuntini, Serena; Reason, Donald C; Granoff, Dan M (2012) Combined roles of human IgG subclass, alternative complement pathway activation, and epitope density in the bactericidal activity of antibodies to meningococcal factor h binding protein. Infect Immun 80:187-94
Reason, Donald; Liberato, Justine; Sun, Jinying et al. (2011) Mechanism of lethal toxin neutralization by a human monoclonal antibody specific for the PA(20) region of Bacillus anthracis protective antigen. Toxins (Basel) 3:979-90
Giuntini, Serena; Reason, Donald C; Granoff, Dan M (2011) Complement-mediated bactericidal activity of anti-factor H binding protein monoclonal antibodies against the meningococcus relies upon blocking factor H binding. Infect Immun 79:3751-9
Reason, Donald; Liberato, Justine; Sun, Jinying et al. (2009) Frequency and domain specificity of toxin-neutralizing paratopes in the human antibody response to anthrax vaccine adsorbed. Infect Immun 77:2030-5
Reason, Donald C; Ullal, Anuska; Liberato, Justine et al. (2008) Domain specificity of the human antibody response to Bacillus anthracis protective antigen. Vaccine 26:4041-7
Zhou, Jianhui; Ullal, Anuska; Liberato, Justine et al. (2008) Paratope diversity in the human antibody response to Bacillus anthracis protective antigen. Mol Immunol 45:338-47