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

> **NIH NIH R01** · ROCKEFELLER UNIVERSITY · 2024 · $862,508

## Abstract

ABSTRACT
Licensed influenza vaccines commonly elicit strain-specific immunity, failing to provide protection against
antigenically distinct strains with the capacity to cause pandemic outbreaks. Therefore, the development of a
universal influenza vaccine with the capacity to elicit lifelong protection against diverse influenza virus strains is
critically needed to prevent future influenza pandemics. Influenza hemagglutinin (HA) represents a key vaccine
target, as it is the major glycoprotein expressed on the surface of influenza virions and mediates viral entry and
fusion. HA comprises two distinct functional domains: (i) the globular head, which is highly variable due to
antigenic drift, and (ii) the stalk domain, which is structurally conserved among diverse influenza strains.
Influenza infection or vaccination commonly elicits immune responses against immunodominant, strain-specific
epitopes on the HA head. By contrast, immune responses against highly conserved epitopes are limited and
short-lived, despite conferring broad and heterologous protection. Refocusing the immune response towards
conserved, immunosubdominant HA epitopes, while avoiding eliciting strain-specific immunity, represents a
promising strategy for the development of a universal influenza vaccine that would confer broad protection
against diverse influenza strains. To achieve this, the proposed studies aim to develop and evaluate novel HA
immunogens, termed mosaic HAs (mHA), in which the immunodominant, strain-specific epitopes at the head
domain have been replaced from those of exotic HAs which humans are naïve, while immunosubdominant,
conserved epitopes have been retained. In previous studies, we have dissected the mechanisms by which
antibodies, through specific interactions of their Fc domains with activating Type I Fcγ receptors (FcγRs), such
as FcγRIIa on dendritic cells and with the Type II FcγR, CD23, on B cells modulate cellular and humoral immunity
against influenza, respectively. Given the immunomodulatory consequences of Fc-FcγR interactions, the
proposed studies will develop Fc-engineered mHA immunogens that will engage and activate specific FcγR
pathways on defined effector cell populations to elicit broad and long-lasting immunity against diverse influenza
strains. We anticipate that the proposed studies will lead to the design, selection, and pre-clinical evaluation of
innovative immunogens with the capacity to confer durable and heterologous protection against influenza. These
studies are expected to have important implications not only for our efforts towards the development of a
universal influenza vaccine, but also provide the framework for the design of vaccines with long-lasting and broad
protection against other viral pathogens, such as SARS-CoV-2.

## Key facts

- **NIH application ID:** 10878418
- **Project number:** 2R01AI145870-06
- **Recipient organization:** ROCKEFELLER UNIVERSITY
- **Principal Investigator:** Peter Palese
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $862,508
- **Award type:** 2
- **Project period:** 2019-06-18 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10878418

## Citation

> US National Institutes of Health, RePORTER application 10878418, Development of vaccination strategies to elicit broadly protective immunity against influenza (2R01AI145870-06). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10878418. Licensed CC0.

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