Impact of aging on human b cell vaccine responses

Active Cooperative Agreement Awarded Last action

Award ID
U01AI180164
Recipient
Awarding agency
Obligated
$2,260,800

Award facts

Assistance listing
93.855 Allergy and Infectious Diseases Research
Completion date 50% complete
Place of performance
Irvine, CA 92697, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
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.

Transactions

Action Obligated Date
Amendment $565,200
Amendment $565,200
Amendment $565,200
Original award $565,200

Quick answers

Who received award U01AI180164?

U01AI180164 was awarded to University Of California Irvine by National Institute of Allergy and Infectious Diseases (National Institutes of Health) on May 6, 2024.

How much is award U01AI180164 worth?

$2,260,800 has been obligated on U01AI180164.

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