# Overcome immunodominance to support the development of universal influenza vaccines

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2024 · $709,236

## Abstract

PROJECT SUMMARY
An ideal "universal flu vaccine" should have the ability to trigger broadly protective antibody and humoral memory
responses against both existing and future influenza viral strains. However, a major obstacle in achieving this
goal is immunodominance in B cell responses, which tend to prioritize dominant epitopes at the expense of
conserved yet subdominant epitopes. In the case of the influenza hemagglutinin (HA), the variable globular head
domain is highly immunodominant over the stem epitope that is much more conserved. To address this challenge,
a Toll-like receptor 7 (TLR7) agonist-based nanoparticle (NP) adjuvant (TLR7-NP) has been developed to induce
prolonged and localized TLR7 signaling in the draining lymph nodes. In contrast to TLR7 agonist formulated with
alum (TLR7-alum), the TLR7-NP adjuvant has demonstrated a remarkable ability to overcome
immunodominance and stimulate a broad antibody response targeting the subdominant HA stem epitope. There
is a critical need to understand the precise mechanisms controlling B cell immunodominance and the breadth of
humoral responses. The goal of this research is to gain mechanistic insights into how adjuvant formulation
influences B cell intrinsic and extrinsic factors that shape immunodominance and the breadth of humoral
responses. The overarching hypothesis is that the interplay between B cell intrinsic and extrinsic factors,
prompted by prolonged TLR signaling through nanoparticle formulated adjuvant, facilitates the recruitment,
selection and effector differentiation of germinal center (GC) B cells specific for the subdominant epitopes. This
hypothesis will be tested through two specific aims. Aim 1 will determine how TLR7-NP impacts
immunodominance, breadth and tolerance across different stages of B cell memory development. The goal of
this aim is to identify the “bottleneck” that has the greatest influence on the immunodominance and breadth of
the humoral response. Aim 2 will elucidate the interplay between extrinsic factors and B cells underlying the
enhancement of antibody breadth by TLR7-NP. In this aim, we will use genetic models to manipulate the
surrounding cell types as well as the microenvironment to investigate how these specific pathways contribute to
the altered B cell immunodominance, a crucial mechanism underlying the breadth induced by TLR7-NP. This
research proposal is innovative because it makes a conceptual advance in understanding the mechanisms
governing the breadth of humoral responses, linking it to the spatiotemporal regulation of signaling through
adjuvant formulation. This research proposal is significant because these insights will not only advance our
understanding of how vaccine adjuvants work but also will empower us to refine vaccine strategies to precisely
manipulate the breadth of B cell response. Ultimately, this will unlock new opportunities for the rational design of
universal influenza vaccines.
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## Key facts

- **NIH application ID:** 10945128
- **Project number:** 1R01AI184891-01
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Wei Luo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $709,236
- **Award type:** 1
- **Project period:** 2024-08-28 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10945128

## Citation

> US National Institutes of Health, RePORTER application 10945128, Overcome immunodominance to support the development of universal influenza vaccines (1R01AI184891-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10945128. Licensed CC0.

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