Anthrax poses a significant threat as an agent of biological warfare. The current anthrax vaccine (AVA) requires multiple doses over an 18 month period. Therefore, in addition to the current vaccine, improved anthrax vaccine strategies will offer the public health. Antibodies to the protective antigen (PA) play an important role in specific immunity to anthrax. However, cell mediated immune responses are also important. Professional antigen presenting dendritic cells (DCs) possess the ability to elicit both humoral and cellular immune responses. These cells are poised to capture pathogens, migrate to draining lymph nodes, and select antigen-specific T cells to regulate T, B, and NK cells, macrophages and eosinophils, all of which may contribute to protective immunity. The objective of this proposal is to develop a novel vaccine strategy targeting anthrax PA directly to DCs. Recently we have shown that DCs induce significant T cell activation in vivo and in vitro. Moreover, our preliminary data demonstrate that recombinant PA activates DCs, inducing up-regulation of co-stimulatory molecules, and LC migration in vivo. We have generated peptides that specifically bind to DC subsets from a phage display library. We hypothesize that targeting PA directly to DCs will increase the levels and duration of a specific immune response resulting in better protection against anthrax. Thus, we will target PA to DCs by fusing it to DC-specific peptides.
The specific aims of this proposal are 1: To determine whether targeting PA specifically to DCs enhances specific immune responses against B. anthracis PA and 2: To test whether PA-DC peptide fusion protein delivered by subcutaneous administration induces strong immune responses in the immune competent cells. This novel vaccine strategy to target specifically immunogenic PA to DCs via DC-binding peptides may enhance the immunogenicity of PA and thus elicit stronger immune responses against PA of B. anthracis.
|Mohamadzadeh, M; Duong, T; Sandwick, S J et al. (2009) Dendritic cell targeting of Bacillus anthracis protective antigen expressed by Lactobacillus acidophilus protects mice from lethal challenge. Proc Natl Acad Sci U S A 106:4331-6|
|Mohamadzadeh, Mansour; Duong, Tri; Hoover, Timothy et al. (2008) Targeting mucosal dendritic cells with microbial antigens from probiotic lactic acid bacteria. Expert Rev Vaccines 7:163-74|
|Mohamadzadeh, Mansour; Coberley, Sadie S; Olinger, Gene G et al. (2006) Activation of triggering receptor expressed on myeloid cells-1 on human neutrophils by marburg and ebola viruses. J Virol 80:7235-44|
|Mohamadzadeh, Mansour; Chen, Lieping; Olinger, Gene G et al. (2006) Filoviruses and the balance of innate, adaptive, and inflammatory responses. Viral Immunol 19:602-12|
|Mohamadzadeh, Mansour; Olson, Scott; Kalina, Warren V et al. (2005) Lactobacilli activate human dendritic cells that skew T cells toward T helper 1 polarization. Proc Natl Acad Sci U S A 102:2880-5|