The bacterium Bacillus anthracis is highly pathogenic because of its stable spore form that resists treatment with antibiotics, its antiphagocytic capsule, and its production of potent toxins. Thus it has been studied as agent of biological warfare for some 60 years and is an extremely effective terrorist weapon. We have recently developed a novel strategy to rapidly produce fully human monoclonal antibodies after immunization and propose to use this technique to develop therapeutic antibodies against anthrax. These antibodies are derived recombinantly from expression of the immunoglobulin variable region genes of early antibodysecreting cells that arise in a massive, transient burst 7 days after immunization. This technology represents a substantial advance in monoclonal antibody production from humans and provides an opportunity to rapidly develop antibody therapies. We have now used this strategy to produce a limited number of antibodies from recipients of the anthrax vaccine. In collaboration with our U19 team we used serological studies to identify several key peptide epitopes that effectively neutralize anthrax toxin activity. The central goal of this Technology Component is to isolate the monoclonal antibodies that target these epitopes. These antibodies will be valuable as research and diagnostic reagents to assess protective immunity, and could ultimately be developed for safe passive immunization or for treatment of anthrax infection. In addition, analyses of monoclonal antibody reactivity may identify protective antibody specificities that are not dominant in the polyclonal response, or that only arise against non-peptide, structural epitopes. Although a vaccine against anthrax exists and is in limited use, primarily for vaccination of military personnel, its effectiveness is at best only """"""""good"""""""". It requires multiple and continued boosts to provide protection, and our U19 group has determined that serum from only half of those immunized can neutralize anthrax toxicity. Thus a second goal of this component is to characterize the induction of long-term B cell immunity (memory) to gain insight into why the vaccine is relatively ineffective in inducing protective immunity.

Public Health Relevance

Inhalation Bacillus anthracis infection remains a significant bioterrorist threat because there are precious few therapies other than antibiotics. Because of the nonspecific symptoms of inhalation anthrax, antibiotics are often given at a very late stage when the patient is already septic. In this Technology Component we will produce antibodies that could be used as a safe alternative treatment or for passive immunization against anthrax.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI062629-09
Application #
8379020
Study Section
Special Emphasis Panel (ZAI1-KS-I)
Project Start
Project End
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
9
Fiscal Year
2012
Total Cost
$333,451
Indirect Cost
$55,962
Name
Oklahoma Medical Research Foundation
Department
Type
DUNS #
077333797
City
Oklahoma City
State
OK
Country
United States
Zip Code
73104
Hu, Zihua; Jiang, Kaiyu; Frank, Mark Barton et al. (2018) Modeling Transcriptional Rewiring in Neutrophils Through the Course of Treated Juvenile Idiopathic Arthritis. Sci Rep 8:7805
Booth, J Leland; Duggan, Elizabeth S; Patel, Vineet I et al. (2018) Gene expression profiling of primary human type I alveolar epithelial cells exposed to Bacillus anthracis spores reveals induction of neutrophil and monocyte chemokines. Microb Pathog 121:9-21
Seshadri, Sudarshan; Pope, Rosemary L; Zenewicz, Lauren A (2018) Glucocorticoids Inhibit Group 3 Innate Lymphocyte IL-22 Production. J Immunol 201:1267-1274
Girton, Alanson W; Popescu, Narcis I; Keshari, Ravi S et al. (2018) Serum Amyloid P and IgG Exhibit Differential Capabilities in the Activation of the Innate Immune System in Response to Bacillus anthracis Peptidoglycan. Infect Immun 86:
Langer, Marybeth; Girton, Alanson W; Popescu, Narcis I et al. (2018) Neither Lys- and DAP-type peptidoglycans stimulate mouse or human innate immune cells via Toll-like receptor 2. PLoS One 13:e0193207
DeVette, Christa I; Andreatta, Massimo; Bardet, Wilfried et al. (2018) NetH2pan: A Computational Tool to Guide MHC Peptide Prediction on Murine Tumors. Cancer Immunol Res 6:636-644
Popescu, Narcis I; Silasi, Robert; Keshari, Ravi S et al. (2018) Peptidoglycan induces disseminated intravascular coagulation in baboons through activation of both coagulation pathways. Blood 132:849-860
More, Sunil; Yang, Xiaoyun; Zhu, Zhengyu et al. (2018) Regulation of influenza virus replication by Wnt/?-catenin signaling. PLoS One 13:e0191010
Fuentes-Mattei, Enrique; Giza, Dana Elena; Shimizu, Masayoshi et al. (2017) Plasma Viral miRNAs Indicate a High Prevalence of Occult Viral Infections. EBioMedicine 20:182-192
Dumas, Eric K; Garman, Lori; Cuthbertson, Hannah et al. (2017) Lethal factor antibodies contribute to lethal toxin neutralization in recipients of anthrax vaccine precipitated. Vaccine 35:3416-3422

Showing the most recent 10 out of 121 publications