In-depth B cell analysis to determine pre-existing B cell immunity against SARS-CoV-2

The B cell-mediated humoral immune response is a major part of the human immune system and shapes disease progression and severity. Hallmark of an effective B cell response is the development of pathogen-specific antibodies after an infection or vaccination. Understanding the B cell response is critical for improving vaccine design and implementation of vaccine- strategies. In the past, pathogen-specific, neutralizing antibodies have been successfully identified and demonstrated to be a promising new therapeutic option to treat infectious diseases. A comprehensive and in-depth B cell receptor repertoire analysis therefore expands our knowledge and provides new insights about how these antibodies evolve and how they can be elicited. In this thesis, I implemented and advanced techniques to study the B cell immune response and applied these to highly relevant infectious diseases. I investigated pathogen-driven alterations in the B cell receptor repertoire and isolated potent and broadly neutralizing antibodies as potential therapeutic agents. To this end, I co-established protocols for B cell subset identification and characterization on a cellular and sequence level by improving FACS sorting strategies and extracting B cell receptor sequence information on a single cell level and from bulk sorted cells. We revealed a convergent antibody evolution against an Ebola virus vaccine and SARS-CoV-2 and demonstrated that elicited antibodies show partly low levels of somatic hypermutation. Moreover, this thesis contributed critical techniques to identify and to analyze novel potential therapeutic antibodies against Ebola virus, HIV-1 and SARS-CoV-2. With the emerge of the COVID-19 pandemic, particular focus was set on the investigation of a pre-existing immunity against SARS-CoV-2 since these findings can be critical for vaccine strategies. Taken together, this thesis provides detailed insights into B cell immune responses against viral infections with important implications for the development of vaccines as well as new drugs for therapy and prevention