Protective Antigen and Toxin Neutralization Antibody Patterns in Anthrax Vaccinees Undergoing Serial Plasmapheresis

Abstract

Recipients of licensed anthrax vaccine (AVA; Biothrax) could serve as a source of hyperimmune plasma and immunoglobulin for therapy and prophylaxis. We measured serum antibodies during serial weekly to biweekly plasmapheresis in 38 individuals previously vaccinated with 4 to 27 doses of AVA. Immunoglobulin G (IgG) to protective antigen (PA) and toxin neutralization assay (TNA) antibody levels were highly correlated (r ‫؍‬ 0.86930 and P < 0.0001 for anti-PA concentration versus TNA concentration). Significant decreases in antibody titer and concentration were observed over time when compared for the number of days from the last AVA injection (P < 0.0001 for both anti-PA and TNA concentration) and for the number of days from the first plasmapheresis (P ‫؍‬ 0.0007 for anti-PA concentration and P ‫؍‬ 0.0025 for TNA concentration). The rate of the decrease in total IgG concentration (half-life [t 1/2 ] ‫؍‬ 198.90 days after first plasmapheresis) was significantly less than the decrease in anti-PA IgG (t 1/2 ‫؍‬ 63.53 days) (P < 0.0001), indicating that the reduction in anti-PA IgG was more likely due to natural decay than plasmapheresis. The time since the last injection and the time after initial plasmapheresis are important elements in considering an optimal schedule for collecting anthrax hyperimmune plasma. Good correlation between IgG to PA and TNA antibodies suggests that the anti-PA enzyme-linked immunosorbent assay can be used as a high-throughput screen for functional immune reactivity in donor plasma units.

Patterns of antibody response in humans to the anthrax vaccine adsorbed (AVA) primary (six-dose) series☆

“…Binding of PA impedes toxin entry into cells, and is important in neutralizing B. anthracis LT in vivo and in vitro [20]. We and others have shown that there is strong correlation between IgG to PA and toxin-neutralizing activity after human infection with virulent anthrax, and vaccination with AVA [21,22].…”

CD1d-Dependent B-Cell Help by NK-Like T Cells Leads to Enhanced and Sustained Production of Bacillus anthracis Lethal Toxin-Neutralizing Antibodies

“…There is a good correlation between PA-specific Ab titers and toxin neutralization by sera from patients who have survived B. anthracis infection (29). Consequently, there is considerable interest in development of efficacious vaccines which incorporate PA as the immunogen but involve fewer immunizations, boost immunological memory, and prolong neutralizing Ab production while stimulating a minimal inflammatory response (28,29).…”

“…The current AVA anthrax vaccine administered to U.S. military personnel consists of the Bacillus anthracis protective antigen (PA) and induces PA-specific antibody (Ab) titers sufficient to neutralize anthrax toxin (28,29). However, the anti-PA Ab titers are not sustained, and individuals require administration of multiple booster vaccines to maintain toxin-neutralizing Ab titers (http://www.anthrax.osd.mil/vaccine/schedule.asp#).…”

A Heterologous Helper T-Cell Epitope Enhances the Immunogenicity of a Multiple-Antigenic-Peptide Vaccine Targeting the Cryptic Loop-Neutralizing Determinant ofBacillus anthracisProtective Antigen

“…These toxins are classic A-B toxins, where lethal factor and edema factor represent the active moieties and protective antigen (PA) represents the cell-binding moiety (5,6,20). Humoral immunity to PA can successfully mediate protection from lethal challenges in animal models of inhalation anthrax, and the protection is correlated with the ability of PA-specific antibodies to neutralize LeTx in vitro in the toxin neutralization assay (TNA) (17,21,22,35,36,41).While PA-specific antibody titer has been shown to correlate with TNA titers in vitro, this relationship demonstrates variability among different studies and in different species (19,37,40,43,48,50). Most PA-specific neutralizing monoclonal antibodies (MAbs) show a more invariable linear relationship between concentration and toxin neutralization (4, 46).…”

“…While PA-specific antibody titer has been shown to correlate with TNA titers in vitro, this relationship demonstrates variability among different studies and in different species (19,37,40,43,48,50). Most PA-specific neutralizing monoclonal antibodies (MAbs) show a more invariable linear relationship between concentration and toxin neutralization (4, 46).…”