For vaccines to be effective, antigens contained in the vaccine mixture must be acquired and presented by antigen presenting cells. Alum-based vaccines often result in the induction of immune responses that are skewed or incomplete. Additionally, immune responses directed against single molecules or peptide fragments in alum are often weak. We have developed a novel strategy for delivering antigen to antigen presenting cells that preliminary studies have shown to be highly effective at augmenting antigen-specific immune responses in vivo and in vitro. Our strategy relies on targeting antigen to Fcgamma receptors (FcgammaR) expressed on antigen presenting cells using novel engineered ligands for FcgammaR (FcRLs) that are composed of linear polymers of the hinge and CH2 (HCH2) regions of IgG. FcRLs have many advantageous features which suggests their potential as a vaccine delivery agents. The goal of the proposed studies is to determine if FcRLs can function as a vaccine delivery system for the purpose of inducing protective immunity using botulinum neurotoxin as a model toxin. To accomplish these goals we propose the: 1). Utilization of FcRLs as a vaccine delivery agent for the induction of immune responses against BoNT/A. 2). Optimization of FcRLs as vaccine delivery agent for BoNT Hc antigens. 3). Characterization of FcRL-induced immune responses to BoNT/A Hc antigens. 4). Characterization of FcRL-induced alterations in antigen presenting cell function.

Our preliminary data are suggestive that using FcRLs to target antigen to APCs represent a sound and effective strategy for the design of new vaccines. The proposed studies will 1). Develop potentially effective immunogens against BoNT. 2) Determine the efficacy of using FcRLs in vaccine development. 3) Establish the utility of targeting antigen to Fc(R as a means of augmenting antigen presentation by APCs and 4) Provide basic information on the role complement in Fc(R mediated internalization The knowledge gained in the course of these studies would have applicability to the establishment of protective immunity against a wide number of pathogens including numerous NIAID Category A, B and C Priority Pathogens and their toxic products. Examples of these include anthrax toxin, ricin and related toxins and the clostridium botulinum neurotoxins.

R21AI058003

2004-09-30

2008-08-31