PROJECT SUMMARY / ABSTRACT The long-term objective of the research proposed here is to establish a novel method for creating vaccines. These vaccines will lead to a highly focused antibody response toward particular epitopes that are known to be the targets of neutralizing monoclonal antibodies (mAbs). If successful, this approach could be applied broadly for the creation of important, new vaccines that protect against infectious disease. The ability to focus the antibody response toward particular epitopes would permit vaccines to be created that elicit neutralizing antibodies, instead of non-neutralizing antibodies. It would also permit creation of vaccines that lead to an antibody response directed against highly conserved regions of an infectious agent, leading to broad spectrum protection against different strains and minimizing the possibility of “escape” by mutant variants. The key starting material for the approach is a mAb that is broadly neutralizing against the infectious agent. In recent decades, many potent, broadly neutralizing mAbs (bnAbs) have been isolated and characterized in detail. Some of these bnAbs (for example, that target influenza virus, Ebola virus and HIV-1) have entered clinical trials to test their efficacy in treating infectious disease and/or to determine whether passively infused mAb can prevent infection. Despite major research funding, however, it has generally not been possible to create vaccines that are capable of eliciting antibodies with properties such as these bnAbs. Here, a simple but radically different approach for creating epitope-focused vaccine candidates is utilized that leverages a tool that has been available all along – the mAb itself. First, binding of the mAb is used to protect the target epitope. Next the surface of the remainder of the antigen is modified to render it non-immunogenic. Finally, the protecting mAb is removed, thereby deprotecting and exposing the unmodified, target epitope. The method is called protect, modify, deprotect (or PMD). Ultimately, this high-risk, high-reward proposal could enable creation of vaccines that elicit an antibody response against any given mAb epitope, and only that epitope.