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142 Steps Towards Epitope-Based Vaccines

Gershoni, Jonathan M

JAIDS Journal of Acquired Immune Deficiency Syndromes: April 2011 - Volume 56 - Issue - p 58
doi: 10.1097/01.qai.0000397328.64740.a5
Abstracts
Free

Department of Cell Research and Immunology, Tel Aviv University, Israel

Successful AIDS vaccines will ultimately need to stimulate both cellular and antibody responses against neutralizing epitopes of HIV. The evidence that such effective-epitopes exist stems from the fact that potent broadly cross neutralizing monoclonal antibodies have been isolated in a number of labs and have proven able to protect monkeys from SHIV challenge in model systems. Hence, a paradigm for rational vaccine design could consist of a number of well defined steps: (i) isolation and characterization of broadly cross neutralizing antibodies, (ii) physical mapping of their corresponding epitopes, (iii) reconstitution of these epitopes, (iv) development of immunogens containing the reconstituted epitopes. Steps one and two have been accomplished to various degrees. Although only a few leading monoclonals have been isolated, they amply prove that neutralizing B-cell epitopes exist in both HIV gp120 and gp41. These have been mapped via a number of methodologies; the most defining is antibody:antigen co-crystallization. Little progress, however, has been made in meeting the challenge of “Step three”, namely reconstitution of functional B-cell epitopes. This is mainly due to the highly complex, discontinuous, conformational nature of such epitopes. How does one extract the critical components of a proven epitope and display them in their proper spatial orientation? Here we describe a practical approach towards epitope reconstitution. For this, bona fide segments of a given epitope are expressed in combinatorial phage display libraries. The segments are connected via a vast collection of random linkers thus creating a library of epitope conformers. The library is then screened against its cognate antibody in order to isolate conformers whose structures are recognizable. Once this is accomplished, the phage displayed reconstituted epitopes can be used to develop immunogens which will be tested for their ability to stimulate the production of neutralizing antibodies in an animal model.

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