# Development of vaccination strategies to elicit broadly protective immunity against influenza

> **NIH NIH R01** · ROCKEFELLER UNIVERSITY · 2020 · $847,458

## Abstract

ABSTRACT
The most effective measure for the prevention of influenza virus infection is vaccination. However, due to ongoing
antigenic drift, current influenza vaccines need annual reformulation to provide sufficient protection. Furthermore,
immune responses elicited upon influenza vaccination are strain-specific and fail to provide protection against
novel seasonal and pandemic viruses, necessitating the development of a universal influenza vaccine with the
capacity to elicit lifelong protection against diverse influenza virus strains. A major target for the development of
protective immunity against influenza is the hemagglutinin glycoprotein (HA), which comprises two distinct
functional domains: the globular head, which participates in viral entry and is subject to antigenic drift, and the
stalk domain, which is highly conserved and mediates viral fusion. Immunodominant antigenic sites on the HA
head elicit high-affinity, strain-specific anti-HA Ab responses, whereas in contrast, Abs against conserved
epitopes can mediate broadly protective activity, but are immunosubdominant. To overcome the inherent
immunodominance of the HA head and refocus immunity towards conserved, cross-protective epitopes, we will
engineer innovative mosaic HA protein immunogens in which HA head antigenic sites will be silenced. Our prior
research demonstrated that vaccination with HA:anti-HA IgG immune complexes (ICs) can modulate adaptive
immunity through specific interactions of the Fc domain of the IgG with Fcγ receptors (FcγR) on the surface of
effector leukocytes. Our in-depth studies revealed that engagement of specific FcγRs: CD23 on B-cells and
FcγRIIa on dendritic cells (DCs), is critical for the induction of high-affinity IgG responses and T-cell immunity,
respectively. Based on this knowledge, we will exploit these pathways to broaden specificity, increase affinity
and select for long-lived humoral and cellular immunity to conserved influenza epitopes. We will design and
evaluate the immunogenicity of IC-based immunogens comprising mosaic HAs and Fc-engineered anti-HA IgGs
with selective affinity for specific human FcγR types. These studies will lead to the development and pre-clinical
evaluation of vaccination strategies to elicit robust and long-lasting antiviral immunity, which could improve the
breadth of current seasonal vaccines, but could also be employed in the development of novel, next-generation
universal influenza virus vaccines.

## Key facts

- **NIH application ID:** 9960417
- **Project number:** 5R01AI145870-02
- **Recipient organization:** ROCKEFELLER UNIVERSITY
- **Principal Investigator:** Peter Palese
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $847,458
- **Award type:** 5
- **Project period:** 2019-06-18 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9960417

## Citation

> US National Institutes of Health, RePORTER application 9960417, Development of vaccination strategies to elicit broadly protective immunity against influenza (5R01AI145870-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9960417. Licensed CC0.

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