The generation of an effective pan-influenza vaccine should induce the following immune memory responses: 1) protective titers of serum antibody that potently neutralizes a wide variety of influenza strains; 2) a robust memory B cell pool that can be rapidly adapted by somatic mutation to neutralize varying influenza strains that evolve in the future;and 3) the requisite T cell mediated memory response to support this adaptation within germinal center reactions. The three projects in this program will work towards these goals using the mAb technology core as a central resource in order to inform antigen and vaccine design. These antibodies will be used to quantify the efficiency of broadly-neutralizing antibodies elicited in mice and to evaluate the ability of human B cell responses to target candidate epitope specificities such as those induced by the long alpha helix of the HA2 molecule and the headless HA construct from Peter Palese's group. The studies proposed will generate large panels of both mouse and human mAbs that may themselves be valuable as therapeutic reagents to treat severe cases of influenza infection. The relative efficacy of these antibodies and thus the epitopes that elicit them will be evaluated in vivo by the Garcia-Sastre project. The requisite T cell epitopes required to elicit broadly protective antibodies will be evaluated by the Ahmed project, using the core to evaluate the spectrum of B cell epitopes supported by T cell epitopes during influenza responses in both mice and humans. The mAb core will be responsible generating both classic mouse hybridomas and recombinant monoclonal antibodies for use by the three projects. The Core will also be responsible for the initial biochemical characterization of both human and mouse monoclonals. Specifically, Project 1 will use the core to generate mAbs against broadly neutralizing epitopes. This project will utilize the core extensively for production of mouse antibodies. Further, the core will provide broadly protective human antibodies to template novel vaccine candidate constructs. Project 2 will explore coordinate epitope specificities in mice lymphoid tissues and human tonsils. The B cell epitopes will be identified through the generation of mouse and human antibodies from the same tissues that TFH cells are isolated. Project 3 will examine the efficacy of mAbs generated by the core for prophylaxis against various influenza virus strains in mice and ferrets. These mAbs will help in evaluating candidate vaccine efficacy and identify mechanisms of neutralization.
The goal of generating a broadly protective vaccine effective against most influenza strains is centered on the specificity of antibodies that can be induced. This core will utilize our specialized approaches to generate and study antibody responses to assist the program projects to both template and evaluate candidate pan-influenza vaccines.
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