# Impact of aging on human B cell vaccine responses

> **NIH NIH U01** · UNIVERSITY OF CALIFORNIA-IRVINE · 2024 · $565,200

## Abstract

PROJECT SUMMARY
As humans age, their immune systems become dysfunctional. Specifically, aging impacts adaptive immunity
leading to reduced response to vaccines. A productive immune response to vaccines is characterized by high
affinity antibodies and an increase in antigen-specific memory B and T cells. Intense research efforts have
determined the role of T cells in aging; however the role of B cells is less clear. We hypothesize that humans,
like mice, have age-related B cells (ABCs) in blood that can be tracked by clonal expansion, and in
within tissue, outcompete important tissue specific B cell types, therefore limiting the capacity of older
adults to respond to vaccines. We have assembled a team that span topic areas and technical expertise to
address difficult questions of human B cell dysfunction with age. We utilize longitudinal and cross-sectional
design to assess B cell aging in blood and lymphoid tissues. Further, we leverage a novel in vitro human tonsil
organoid model we developed that allows mechanistic testing of age-induced B cell decline of vaccine
responses, a feat previously impossible. In Aim 1, we will identify human ABCs by mapping dysregulation of
phenotypic and functional B cell signatures over time. We hypothesize that ABCs are memory B cells that
accumulated epigenetic changes, leading to a transcriptional program consisting of muted BCR
responsiveness, dysregulated expansion, and defective function. We will analyze peripheral blood B cells and
serum from a healthy aged longitudinal cohort using high-parameter flow cytometry and bulk RNA sequencing
and multiplexing to track changes in B cell subsets, transcriptional profiles, BCR repertoires, and cytokine and
antibody secretion. In Aim 2, we will target age-related mechanisms of lymphoid tissue B cell dysfunction to
improve effective flu vaccine responses. ABCs are thought to derive from expansion of memory B cells.
Therefore, we hypothesize that lymphoid tissues with high antigen exposure will have higher prevalence of
ABCs and increased signatures of aging. Furthermore, we anticipate that targeting ABCs using a human tonsil
organoid platform will improve flu vaccine responses. With unparalleled access to multiple post-mortem
lymphoid tissues, we will compare B cells from young and older adults. We will use high parameter flow
cytometry to enumerate B cell populations and perform single cell RNA sequencing on sorted B cells across
human blood and tissues. Additionally, we will assess metabolism and cytokine secretion of aging B cells
across tissues using extracellular flux analysis and multiplex cytokine profiling. Lastly, we will use a novel in
vitro human tonsil organoid model to determine the cellular and molecular mediators of impaired vaccine
responses. Understanding how age impacts B cell function will allow for improvement of vaccine design to
increase B cell antibody responses, and therefore better protect the aging population of the world.

## Key facts

- **NIH application ID:** 10786010
- **Project number:** 1U01AI180164-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Dequina Angelina Nicholas
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $565,200
- **Award type:** 1
- **Project period:** 2024-05-06 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10786010

## Citation

> US National Institutes of Health, RePORTER application 10786010, Impact of aging on human B cell vaccine responses (1U01AI180164-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10786010. Licensed CC0.

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