Edema toxin (ET), composed of edema factor (EF) and protective antigen (PA), is a virulence factor of Bacillus anthracis that alters host immune cell function and contributes to anthrax disease. Anthrax vaccine precipitated (AVP) contains low but detectable levels of EF and can elicit EF-specific antibodies in human recipients of AVP. Active and passive vaccination of mice with EF can contribute to protection from challenge with Bacillus anthracis spores or ET. This study compared humoral responses to ET in recipients of AVP (n 33) versus anthrax vaccine adsorbed (AVA; n 66), matched for number of vaccinations and time postvaccination, and further determined whether EF antibodies elicited by AVP contribute to ET neutralization. AVP induced higher incidence (77.8%) and titer (229.8 58.6) of EF antibodies than AVA (4.2% and 7.8 8.3, respectively), reflecting the reported low but detectable presence of EF in AVP. In contrast, PA IgG levels and ET neutralization measured using a luciferase-based cyclic AMP reporter assay were robust and did not differ between the two vaccine groups. Multiple regression analysis failed to detect an independent contribution of EF antibodies to ET neutralization in AVP recipients; however, EF antibodies purified from AVP sera neutralized ET. Serum samples from at least half of EF IgG-positive AVP recipients bound to nine decapeptides located in EF domains II and III. Although PA antibodies are primarily responsible for ET neutralization in recipients of AVP, increased amounts of an EF component should be investigated for the capacity to enhance next-generation, PA-based vaccines.
Bibliographical noteFunding Information:
This work was supported by the National Institutes of Health (NIH) grant numbers U19 AI062629, U54 GM104938, and P30 GM103510 and the OMRF Lou C. Kerr Chair in Biomedical Research.
We are grateful to the Walter Reed National Military Medical Center Immunization Healthcare Branch Vaccine Safety and Evaluation Section (formerly Walter Reed Army Medical Center Vaccine Healthcare Centers Network/Allergy-Immunology Research Team), the Fort Bragg Immunization Healthcare Branch Regional Vaccine Safety Hub Research Team, all of the study participants, Tim Mather for assistance with the EF crystal structure, Ken Humphries for use of his luminometer, Virginia Roberts for clinical coordination, and Rebecca Sparks, Philip Cox, Emily Muns, Clayton Nelson, Linda Ash, Wendy Klein, Krista Bean, and Maria Sargent for technical assistance. Local protocol development and management was supported by Walter Reed National Military Medical Center Immunization Healthcare Branch (formerly Walter Reed Army Medical Center Vaccine Healthcare Centers Network/Allergy-Immunology Department) and Womack Army Medical Center, Fort Bragg Regional Vaccine Safety Hub. Human anti-AVA reference serum (AVR801, NR-719) was obtained through the NIH Biodefense and Emerging Infections Research Repository, National Institute of Allergy and Infectious Diseases.
Copyright © 2017 American Society for Microbiology. All Rights Reserved.
- Bacillus anthracis
- Edema toxin