At the present time protection from anthrax exposure is largely based upon vaccination of those considered at risk, particularly including active duty military personnel in combat theaters, veterinarians in certain settings, and laboratory workers. The anti-Protective Antigen (PA) antibody level is widely considered the most easily accessible surrogate for a protective response from anthrax infection. We propose to apply the modern reverse genetics approach to this immune response in an effort to understand the genetic contributors to this vaccine response, in particular, and in the anticipation that genetic variants important in the response to anthrax will also be important in other successful vaccinations. To our knowledge modern reverse genetic tools have not been previously applied to develop a basic understanding of the genetic contribution to any vaccination, much less to anthrax. In three preliminary studies supported during the first grant cycle we have evaluated the relationship between the quantitative levels of anti-PA antibodies to 500,000 single nucleotide polymorphisms (SNPs) covering the autosomes and X chromosome in over 300 participants vaccinated with Anthrax Vaccine Absorbed (AVA). A number of candidate genes have been thereby identified, which warrant replication and fine mapping studies, the first of which is underway. We propose to expand the scope of the genome scan to 1,500,000 screening SNPs, and also to perform replication and fine mapping studies, to secure the participation of a total of 4000 vaccinated subjects, and to evaluate the genomics of the resulting genes. While it has taken a considerable effort to collect the samples necessary for this analysis, with samples now in hand, preliminary data available, and a now constant stream of new samples, the project is now ripe for substantial progress. The results of the project should identify many new genes important for the future development of vaccines and for understanding resistance to lethal anthrax.

Public Health Relevance

Few of the genes that regulate the immune response to vaccination are known. Our preliminary data and proposed increased capacity to screen SNPs promise to reveal many genetic variants governing the human response to AVA, the antrhax vaccine. The accurate identification of these genetic factors will lead to the production of a more effective vaccine. Furthermore, gene identification will provide a better understanding of vaccine efficacy and how adverse effects and non-response can be avoided.

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 #
8379016
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
$282,787
Indirect Cost
$47,459
Name
Oklahoma Medical Research Foundation
Department
Type
DUNS #
077333797
City
Oklahoma City
State
OK
Country
United States
Zip Code
73104
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
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
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