# NIH grant: Exposing versus Hiding: A Novel Nanoplatform for Nasal Universal Flu Vaccines (1R21AI202743-01) — retained record

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NIH grant 1R21AI202743-01: Exposing versus Hiding: A Novel Nanoplatform for Nasal Universal Flu Vaccines
Institute: {'code': 'AI', 'abbreviation': 'NIAID', 'name': 'National Institute of Allergy and Infectious Diseases', 'admin_org_id': '12500003', 'admin_funding_url': ''}. PI: Baozhong  Wang. Award: $197552.
Start: 2026-08-07T00:00:00.
Project Summary
To effectively prevent seasonal and pandemic influenza, we need a universal influenza vaccine to protect
both the respiratory tract and the system against various viruses. An ideal solution would be a nasal vaccine
that targets conserved parts of the virus shared across many strains. Unfortunately, current cross-
protective vaccines in development are only administered by injection and do not provide strong cross-
protection in preclinical and clinical trials. These limitations may arise from two challenges: a lack of safe nasal
or mucosal delivery platforms and adjuvants, and the reduced immune response when using only the
conserved viral components without their strain-specific counterparts.
Some vaccine candidates target the conserved stalk region of the hemagglutinin (HA) protein. These have
shown limited success, triggering immune responses like ADCC and ADCP but not high-affinity antibody
responses, such as broadly cross-neutralizing antibodies. Also, injected vaccines do not activate key local
immune defenses, like secretory IgA on the surface of the respiratory tract and lung resident memory T cells,
which are vital for fast recall immune responses and broad protection in a secondary influenza infection.
Our recent research showed that nanosized extracellular vesicles (EVs) from mammalian cells carry sialic
acid receptors and can bind HA in a way that flips its orientation—hiding the variable head and exposing the
conserved stalk. These “inverted HA” (iHA) EVs, when administered nasally, elicited strong immune
responses in mice without the need for an adjuvant. However, the challenges for the iHA EV vaccine platform
include low EV yield from cell culture, unpredictable incorporation of HA receptors into EVs, and unstable (non-
covalent) HA-receptor interactions. To address these challenges, we will develop a novel plug-and-play EV
platform and display iHA on the surface of the EVs using rapid and stable SpyCatcher/SpyTag conjugation.
We will develop a simple, low-cost nasal influenza vaccine that protects against various strains.
Aim 1: Develop and evaluate iHA EVs for influenza A and B, assess their physical and biochemical
characteristics, and study their distribution and antigen-depot effects in mice.
Aim 2: determine whether the new iHA EV intranasal immunization enhances antibody responses specific to
the HA stalk in both local and systemic compartments, and if the immunity protects mice against different
virus challenges.
This approach could produce a universal flu vaccine that is easy to use via nasal drops. The new plug-and-
play nanoplatform can be tailored to display and orient different antigens or therapeutics for mucosal
applications.
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