Systems biological assessment of B cell responses to vaccination

ABSTRACT – Project 3
The focus of Project 3 is to study antigen-specific B cell and plasma cell responses in the context of two timely
and fundamental topics in vaccinology: (i) Immunology of COVID-19 vaccines, and (ii) the impact of the
microbiota on immune responses to vaccination. The COVID-19 pandemic caused by the novel coronavirus
SARS-CoV-2 (CoV-2), and the vaccines developed to combat this pathogen, have underscored a need for
greater understanding of primary antibody responses in humans. We will use a systematic panel of cutting-
edge humoral immunity analyses to thoroughly characterize antibodies elicited by two CoV-2 vaccines,
and the B cell and plasma cell clonal populations required for B cell memory and sustained antibody
titers. Our focus will be on the serological, B cell and plasma cell responses elicited by a lipid nanoparticle mRNA
vaccine (Pfizer-BioNTech), and a Matrix M-adjuvanted recombinant protein vaccine (Novavax). Combining these
analyses with studies of innate immunity (Project 1) and T cell (Project 2) responses to these vaccines should
highlight cellular mechanisms correlated with the strength and durability of antibody responses. Rare serious
anaphylactoid adverse reactions have been reported for mRNA vaccines, particularly in individuals with a history
of food allergy, and those with IgG antibodies specific for polyethylene glycol (PEG). We will examine potential
B cell contributions to these anaphylactoid reactions, using specimens from affected individuals who
received SARS-COV-2 mRNA vaccines. Finally, we will address the role of the microbiome on humoral
immunity to vaccination, with a similar strategy of serological, memory B cell and plasma cell analyses
in participants with or without temporarily ablated microbiota following antibiotic treatment. Of particular
importance in the aforementioned studies, we will not only analyze peripheral blood B cells and plasmablasts,
but also monitor lymph node germinal center reactions by fine-needle aspiration, and sample bone
marrow plasma cells in the same participants, to comprehensively study humoral immunity to
vaccination in humans.
The combined impact of these investigations will likely be clinically significant in guiding the development of
future vaccination strategies by uncovering the B cell and plasma cell specificities, differentiation pathways, and
longevity stimulated by new SARS-CoV-2 vaccine platforms, and in clarifying the role of the microbiome in
vaccine responses to novel antigens.

Grant Number: 5U19AI167903-05
NIH Institute/Center: NIH
Principal Investigator: Scott Boyd