ORCID
0000-0002-6262-4260
Date of Award
4-18-2024
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
Abstract
Vaccination is the best defense against infection, but highly variable and evolving pathogens like influenza virus pose a significant immunological challenge for vaccine design. An ideal influenza virus vaccine should elicit a durable and broadly cross-reactive antibody response. However, the development of cross-reactive antibodies is hindered by the high degree of antigenic variation among influenza viruses, particularly in the surface glycoprotein hemagglutinin (HA), which is the main target of vaccine-induced responses. Successful vaccination works by driving the differentiation of antigen-specific B cells into short-lived, antibody-secreting plasmablasts (PBs) and long-lived populations of memory B cells (MBCs) and bone marrow plasma cells (BMPCs). High-affinity MBCs and BMPCs are produced in germinal centers (GCs), where antigen-stimulated B cells undergo iterative rounds of somatic hypermutation (SHM) and proliferation followed by affinity-based selection. Evidence from mice and humans suggests that GCs are crucial for increasing antibody breadth through the recruitment of diverse B cell clones. Therefore, extending the duration of the GC reaction may increase the production of high-affinity and diversified MBCs and BMPCs. However, it remains unclear whether influenza virus vaccines can elicit persistent GCs in humans, how those GCs influence the B cell repertoire, and which factors regulate GC persistence and selection. In this thesis, I show that persistent GC reactions induced by seasonal influenza virus vaccination in humans support the maturation of responding B cells, enhancing antibody affinity and breadth. I further explore the GC-driven antibody response in humans after seasonal influenza virus vaccination by characterizing HA head-specific monoclonal antibodies isolated from GC B cells of an immunized individual. Finally, I present preliminary work suggesting antibodies modulate GC duration and clonal diversity using mice that lack secreted IgG1 antibody. This work elucidates the dynamics of the GC response after vaccination and suggests that inducing persistent GC reactions that allow for B cell repertoire diversification is critical for rational vaccine design to highly variable pathogens like influenza virus.
Language
English (en)
Chair and Committee
Ali Ellebedy
Recommended Citation
McIntire, Katherine Marie, "Germinal Center Persistence Diversifies B Cell Responses to Vaccination" (2024). Arts & Sciences Electronic Theses and Dissertations. 3047.
https://openscholarship.wustl.edu/art_sci_etds/3047