2 research outputs found
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Understanding Antigenic Variability by Building Novel Deep Mutational Scanning Tools
The immune system is regulated by protein-protein interactions. When a viral infection is detected, the immune system responds by generating antibodies that can neutralize the viral proteins. Meanwhile the virus replicates, generating new strains that could escape such neutralization. Then, the race begins, not only between the virus and the adaptive immune system, but also against the scientists who are developing antibody therapies and vaccines.
For the development of effective therapeutics and vaccine immunogens, the functional sequence space of the binding protein has to be studied. Current methods rely on the study of existing variants of a viral glycoprotein. However, with every emerging variant, new therapeutics and vaccine immunogens have to be developed. In this thesis I have used deep mutational scanning coupled with next generation sequencing to build tools that will contribute to prospectively map the surface of a protein. I hypothesize that being able to identify escape mutants on the developed therapies as well as characterizing the tolerable sequence variation of the targeted protein will contribute to the generation of new and more potent therapeutics and vaccine immunogens.</p
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One-shot identification of SARS-CoV-2 S RBD escape mutants using yeast screening
The potential emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) escape mutants is a threat to the efficacy of existing vaccines and neutralizing antibody (nAb) therapies. An understanding of the antibody/S escape mutation landscape is urgently needed to preemptively address this threat. Here we describe a rapid method to identify escape mutants for nAbs targeting the S receptor binding site. We identified escape mutants for five nAbs, including three from the public germline class VH3-53 elicited by natural coronavirus disease 2019 (COVID-19) infection. Escape mutations predominantly mapped to the periphery of the angiotensin-converting enzyme 2 (ACE2) recognition site on the RBD with K417, D420, Y421, F486, and Q493 as notable hotspots. We provide libraries, methods, and software as an openly available community resource to accelerate new therapeutic strategies against SARS-CoV-2.
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