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.
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.
|Morris, D L; Fernando, M M A; Taylor, K E et al. (2014) MHC associations with clinical and autoantibody manifestations in European SLE. Genes Immun 15:210-7|
|Garman, Lori; Smith, Kenneth; Farris, A Darise et al. (2014) Protective antigen-specific memory B cells persist years after anthrax vaccination and correlate with humoral immunity. Toxins (Basel) 6:2424-31|
|Garman, Lori; Vineyard, Amanda J; Crowe, Sherry R et al. (2014) Humoral responses to independent vaccinations are correlated in healthy boosted adults. Vaccine 32:5624-31|
|Lupu, Florea; Keshari, Ravi S; Lambris, John D et al. (2014) Crosstalk between the coagulation and complement systems in sepsis. Thromb Res 133 Suppl 1:S28-31|
|Joshi, Sunil K; Lang, Mark L (2013) Fine tuning a well-oiled machine: Influence of NK1.1 and NKG2D on NKT cell development and function. Int Immunopharmacol 17:260-6|
|Lee, Benjamin C; Mayer, Chad L; Leibowitz, Caitlin S et al. (2013) Quiescent complement in nonhuman primates during E coli Shiga toxin-induced hemolytic uremic syndrome and thrombotic microangiopathy. Blood 122:803-6|
|Dumas, Eric K; Nguyen, Melissa L; Cox, Philip M et al. (2013) Stochastic humoral immunity to Bacillus anthracis protective antigen: identification of anti-peptide IgG correlating with seroconversion to Lethal Toxin neutralization. Vaccine 31:1856-63|
|Sun, Dawei; Popescu, Narcis I; Raisley, Brent et al. (2013) Bacillus anthracis peptidoglycan activates human platelets through FcýýRII and complement. Blood 122:571-9|
|Chiu, Christopher; Wrammert, Jens; Li, Gui-Mei et al. (2013) Cross-reactive humoral responses to influenza and their implications for a universal vaccine. Ann N Y Acad Sci 1283:13-21|
|Smith, Kenneth; Muther, Jennifer J; Duke, Angie L et al. (2013) Fully human monoclonal antibodies from antibody secreting cells after vaccination with Pneumovaxýý23 are serotype specific and facilitate opsonophagocytosis. Immunobiology 218:745-54|
Showing the most recent 10 out of 75 publications