title: Anthrax vaccination induced anti-lethal factor IgG: fine specificity and neutralizing capacity.
abstract: The efficacy biomarker of the currently licensed anthrax vaccine (AVA) is based on quantity and neutralizing capacity of anti-protective antigen (anti-PA) antibodies. However, animal studies have demonstrated that antibodies to lethal factor (LF) can provide protection against in vivo bacterial spore challenges. Improved understanding of the fine specificities of humoral immune responses that provide optimum neutralization capacity may enhance the efficacy of future passive immune globulin preparations to treat and prevent inhalation anthrax morbidity and mortality. This study (n=1000) was designed to identify AVA vaccinated individuals who generate neutralizing antibodies and to determine what specificities correlate with protection. The number of vaccine doses, years post vaccination, and PA titer were associated with in vitro neutralization, reinforcing previous reports. In addition, African American individuals had lower serologic neutralizing activity than European Americans, suggesting a genetic role in the generation of these neutralizing antibodies. Of the vaccinated individuals, only 69 (6.9%) had moderate levels of anti-LF IgG compared to 244 (24.4%) with low and 687 (68.7%) with extremely low levels of IgG antibodies to LF. Using overlapping decapeptide analysis, we identified six common LF antigenic regions targeted by those individuals with moderate levels of antibodies to LF and high in vitro toxin neutralizing activity. Affinity purified antibodies directed against antigenic epitopes within the PA binding and ADP-ribotransferase-like domains of LF were able to protect mice against lethal toxin challenge. Findings from these studies have important implications for vaccine design and immunotherapeutic development.
authors.affiliation: Oklahoma Medical Research Foundation, 825 N.E. 13th Street, Oklahoma City, OK 73104, USA.
authors.forename: Sherry R
authors.initials: SR
authors.lastname: Crowe
authors.forename: Lori
authors.initials: L
authors.lastname: Garman
authors.forename: Renata J M
authors.initials: RJ
authors.lastname: Engler
authors.forename: A Darise
authors.initials: AD
authors.lastname: Farris
authors.forename: Jimmy D
authors.initials: JD
authors.lastname: Ballard
authors.forename: John B
authors.initials: JB
authors.lastname: Harley
authors.forename: Judith A
authors.initials: JA
authors.lastname: James
mesh_terms: D000328:Adult; D001741:Black or African American; D000818:Animals; D022122:Anthrax Vaccines / Q000276:immunology*; D000907:Antibodies, Bacterial / Q000097:blood; D057134:Antibodies, Neutralizing / Q000097:blood; D000917:Antibody Formation; D000918:Antibody Specificity / Q000276:immunology*; D000942:Antigens, Bacterial / Q000032:analysis / Q000276:immunology*; D001408:Bacillus anthracis / Q000276:immunology; D001427:Bacterial Toxins / Q000032:analysis / Q000276:immunology*; D023381:Endpoint Determination; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood* / Q000276:immunology; D008297:Male; D051379:Mice; D009500:Neutralization Tests
chemical_list: D022122:Anthrax Vaccines; D000907:Antibodies, Bacterial; D057134:Antibodies, Neutralizing; D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D007074:Immunoglobulin G; C030325:anthrax toxin