B cell dynamics and immune memory formation in human vaccination

Fred Hutchinson Cancer Center, Seattle WA

Investigators

Abstract

PROJECT SUMMARY Vaccination prevents millions of deaths each year by generating protective immunological memory against pathogens, mediated by long-lived memory B and plasma cells. Diverse B cell populations emerge after vaccination, including CD11c+CD21lo atypical B cells, which are primed for plasma cell differentiation and antigen presentation. However, the relationships between early vaccine-responsive B cell subsets and the long-lived memory B and plasma cells that provide durable immune protection have not been established in humans. Further, novel immunostimulatory adjuvants increase the durability and breadth of vaccine responses, but head-to-head comparisons of their effects on human B cell differentiation are lacking. Insufficient knowledge of the functional relevance and relationships among human B cell subsets and how they are modulated by adjuvants impedes the rational design of vaccines to induce protective immunological memory. Here, we will systematically interrogate human B cell, plasma cell, and antibody responses after HIV vaccination and dissect the mechanisms of their induction in a human immune organoid model. Our unique vaccine cohort is comprised of four groups receiving the same immunogen with a different adjuvant and includes sampling of lymph nodes, where memory B and plasma cells differentiate from germinal center B cells, and bone marrow, where long-lived plasma cells reside. I hypothesize that the adjuvant, 3M-052-AF, will direct atypical B cells towards a germinal center fate, yielding more potent and durable antibody responses. To test this hypothesis, I will leverage our team’s extensive expertise in human B cell biology, vaccinology, and the application of antigen-specific systems immunology tools. I aim to: (1) identify which vaccine-response B cell populations are clonally related to long-lived populations and predict durable immune responses; (2) evaluate the influence of four adjuvants on B cell and antibody responses; and (3) determine the impact of adjuvant on cell phenotype, germinal center organization, and B cell receptor repertoire in a human immune organoid model. To achieve these research aims and establish myself as an independent investigator, I have devised complementary career development goals: (1) expand B cell biology domain knowledge and scientific network; (2) develop expertise in human immune organoid experimentation; and (3) cultivate skills necessary to lead an independent research group. My mentors are Dr. Evan Newell, a systems immunologist, and Dr. Julie McElrath, Director of the HIV Vaccine Trials Network Laboratory, and my advisory committee is comprised of experts in B cell biology, immune organoids, vaccinology, and computational biology. This adept team will provide guidance on both research aims and career development goals, complementing a series of workshops and courses that I have identified to develop the skills and knowledge to lead my own research group.