Antibody feedback on B cell response to vaccination

ABSTRACT Since 2020, over 600 million COVID-19 vaccinations and 500 million influenza vaccinations have been administered in the United States. These vaccines have saved millions of lives by inducing the differentiation and maturation of antigen-specific B cells into antibody-secreting cells, resulting in the generation of high-affinity, protective antibodies. However, little is known about how these antibodies could regulate the ongoing B cell response or subsequent responses to vaccination. Notably, a durable B cell response that produces long-lived antibody-secreting plasma cells and poised memory B cells relies on the processes of affinity maturation and clonal expansion, which occur in anatomical structures called germinal centers (GCs). This proposal aims to provide insight into antibodies' role in regulating germinal center responses. This is a particularly important concept for vaccinations that occur in the context of pre-existing humoral immunity, as in seasonal influenza or COVID-19 booster vaccinations. In Aim 1, the hypothesis of antibody feedback on vaccine-elicited GC B responses will be tested in a newly generated mouse model where IgG1 antibody secretion can be inducibly blocked. The GC response's quality, magnitude, and duration will be characterized in primary and heterologous boost systems. In Aim 2, the same overarching hypothesis will be examined in a human rabies vaccination model. Here, the impact of polyclonal rabies immunoglobulin administration on vaccine-induced GC B cells will be examined for epitope specificity, magnitude, and kinetics changes. Additionally, GC products, long-lived memory B cells, and bone marrow plasma cells will be characterized in the presence and absence of exogenous antibodies. The overall goal of this proposal is to test hypotheses of antibody feedback on GC B cells in complementary systems that combine unique mechanistic probing in mice with authentic human vaccine responses. These findings will have broad public health implications for the millions of vaccinations administered yearly in the United States. During the fellowship, the applicant will acquire fundamental skills that will serve as a steppingstone toward becoming an independent investigator in vaccine research. This will include developing expertise in both rodent and human vaccination models. As described in the proposed training plan, the applicant will be supported by Drs. Ellebedy and Diamond who have demonstrated experience in B cell vaccine responses and mentorship of scientific trainees. With Washington University's track record of excellence in training immunologists and physician-scientists, the applicant will be well-equipped for success in their training towards becoming a physician-scientist.