# Investigating the development and clonal dynamics of broadly neutralizing B cells against influenza viruses > **NIH NIH K99** · UNIVERSITY OF CHICAGO · 2021 · $103,503 ## Abstract PROJECT SUMMARY/ABSTRACT Broadly neutralizing antibodies against the influenza virus surface glycoprotein hemagglutinin (HA) can provide protection from nearly all influenza viruses. However, broadly neutralizing antibodies are rarely induced by vaccination and instead, most antibodies target variable epitopes of the influenza virus HA head domain that only provide narrow protection against a few influenza virus strains. The fundamental mechanisms dictating B cell immunodominance, which B cell specificities are recalled upon virus exposure, remain largely unknown. We identified that first exposure to a novel influenza virus robustly induced antibodies against four broadly neutralizing epitopes of HA. However, repeated exposure to the same virus preferentially drove the recruitment of antibodies targeting variable epitopes of the HA head. Notably, my studies identified that antibodies targeting broadly neutralizing epitopes are enriched for polyreactivity, the ability of a single antibody to bind to multiple molecularly distinct antigens, including foreign and self-antigens. Furthermore, polyreactive naïve B cells targeting broadly neutralizing epitopes are preferentially selected into the memory B cell pool to provide defense against novel pandemic-threat influenza viruses. Based on my preliminary data, I hypothesize that HA epitope specificity influences B cell development, differentiation, and inter-clonal competition, which leads to differences in B cell immunodominance. B cell immunodominance may be dictated by three independent processes: 1) B cells targeting broadly neutralizing epitopes may undergo clonal deletion or become anergic as a result of being polyreactive (Aim 1), 2) B cells targeting broadly neutralizing epitopes differentiate into short-lived B cell subsets as opposed to long-lived B cell subsets (Aim 2), and 3) B cells targeting variable epitopes outcompete B cells targeting broadly neutralizing epitopes (Aim 3). To test these aims, I will use CRISPR/Cas9 to generate B cell receptor knock-in mice expressing the germline version of human monoclonal antibodies targeting four broadly neutralizing epitopes of HA and two variable epitopes of HA. To test Aim 1, I will evaluate B cell development and B cell signaling potential of each B cell receptor knock-in line by generating mixed bone marrow chimeras. In Aim 2, I will determine if epitope specificity shapes B cell differentiation potential by immunizing mice that receive a B cell adoptive transfer from each B cell receptor knock-in line and tracking B cell differentiation and affinity maturation. In Aim 3, I will determine whether B cells targeting a variable epitope outcompete B cells targeting a broadly neutralizing epitope within the germinal center by tracking germinal center responses in HA- immunized mice that have received adoptively transferred B cells targeting each epitope. Knowledge gained from this research will provide critical insight into how broadly neutralizing B... ## Key facts - **NIH application ID:** 10191161 - **Project number:** 1K99AI159136-01 - **Recipient organization:** UNIVERSITY OF CHICAGO - **Principal Investigator:** Jenna Guthmiller - **Activity code:** K99 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2021 - **Award amount:** $103,503 - **Award type:** 1 - **Project period:** 2021-07-22 → 2022-06-30 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10191161 ## Citation > US National Institutes of Health, RePORTER application 10191161, Investigating the development and clonal dynamics of broadly neutralizing B cells against influenza viruses (1K99AI159136-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10191161. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*