# B and Tfh cell dynamics underlying durable antibody responses to flu vaccine in children

> **NIH NIH U01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $614,745

## Abstract

Abstract
Seasonal influenza infection is a major health issue in the United States with children facing increased
susceptibility to illness and death. Quadrivalent inactivated influenza vaccine (IIV4) is recommended for the
prevention of influenza in children. However, influenza vaccine protection is currently insufficient with vaccine
effectiveness from 2019-2020 estimated to be 39%. The primary driver of protection provided by influenza
vaccines are serum antibodies (Abs). T Follicular helper cells (TFH) are a subset of CD4+ T cells that interact with
activated B cells in germinal centers (GCs) to promote selection of higher affinity B cell clones, generated by
somatic hypermutation. Such clones give rise to memory B cells as well as precursors of long-lived plasma cells
(LLPCs), the latter account for durable Ab titers. Our preliminary results in a mouse model suggest that that
LLPC precursors, with a distinctive genomic profile, are preferentially generated at late phases of a sustained
GC response. We hypothesize that sustained TFH dependent GC B cell responses are required for generation of
human LLPC precursors and therefore durable Ab responses after vaccination. We propose to utilize PBMC and
serum samples, from a unique cohort of children and young adults that were administered cell-based IIV4, for
high dimensional and multi-omic analyses, so as to predict and infer latent factors and gene networks that may
underlie the generation of long-lived PCs and therefore durable Ab responses. We will use samples from selected
vaccinees in the clinical trial who mounted significant responses by d28 which were either durable (d365 titers
of Abs dropped less than 2-fold when compared with d28 titers) or waned substantially (returned to near
baseline). We will perform multi-parameter FACS based immune profiling of PBMCs with an emphasis on
activated cTFH and HA-specific B cells, cytokine profiling using MSD multiplex platform and single cell genomic
profiling using 10X multiome (scRNA-seq+scATAC-seq) of cTFH, and PC precursors at d28. These datasets will
be analyzed using state of the art and novel machine learning and computational genomics algorithms, to
delineate latent factors and gene networks, that are predictive of and may control, respectively, the generation
of LLPC precursors. Additionally, the genomic datasets are anticipated to provide the first single cell genomic
snapshots of human LLPC precursors.

## Key facts

- **NIH application ID:** 10764435
- **Project number:** 1U01AI179514-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** John F Alcorn
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $614,745
- **Award type:** 1
- **Project period:** 2024-04-01 → 2029-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10764435

## Citation

> US National Institutes of Health, RePORTER application 10764435, B and Tfh cell dynamics underlying durable antibody responses to flu vaccine in children (1U01AI179514-01). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10764435. Licensed CC0.

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