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NIH grant 1R01AI201635-01: Using albumin-hitchhiking intranasal vaccines to enhance immune protection against infectious disease
Institute: {'code': 'AI', 'abbreviation': 'NIAID', 'name': 'National Institute of Allergy and Infectious Diseases', 'admin_org_id': '12500003', 'admin_funding_url': ''}. PI: Brittany L Hartwell. Award: $687661.
Start: 2026-07-23T00:00:00.
PROJECT SUMMARY
To combat the global HIV epidemic as well as persisting threats such as SARS-CoV-2, immunization strategies
are needed that elicit protection at mucosal portals of pathogen entry. However, traditional parenteral vaccines
that are injected typically elicit poor mucosal immunity. While vaccination at mucosal surfaces is known to be an
effective strategy to activate protective mucosal immunity, delivery of vaccine components across mucosal
barriers has been a major challenge for mucosal vaccine development. Development of technologies to
overcome barriers to mucosal delivery while meeting safety and efficacy requirements of prophylactic vaccines
remains an urgent unmet need. While mucosal barriers are very good at keeping most vaccine components ‘out’,
the endogenous protein albumin is known to be very good at getting ‘in’. Albumin, a major blood protein also
present in mucosal fluids, is constitutively transcytosed across mucosal epithelium through interactions with the
neonatal Fc receptor (FcRn) while functioning in vivo as a fatty acid transporter. Exploiting this biology, we
recently developed a novel immunoengineering strategy of ‘albumin hitchhiking’ to promote mucosal immunity
using an intranasal vaccine consisting of protein immunogens conjugated to an albumin-binding polymer-lipid
tail, forming ‘amph-proteins’. Amph-proteins exhibit enhanced FcRn-dependent uptake into nasal mucosal
tissue, leading to enhanced local immune responses in the nasal-associated lymphoid tissue (NALT) and robust
long-lasting systemic and mucosal humoral responses in tandem. These results suggest that employing amph-
vaccines to deliver antigen (Ag) and adjuvant across mucosal epithelium is a promising strategy to promote
mucosal immunity against infectious diseases. Motivated by these findings, here we propose to further develop
the amph-vaccine platform for mucosal delivery of a range of immune cargo (antigens and adjuvants) while
identifying molecular and cellular mechanisms of action, immune correlates of protection, and the role of vaccine
dosing and kinetics in mucosal associated lymphoid tissue (MALT) for promoting functional protective immunity
in translational mouse models through the following aims. Aim 1: Identify molecular properties and kinetic
mechanisms of intranasal amphiphile-antigen vaccines that drive mucosal humoral immune activation. Aim 2:
Evaluate immunogenicity, adjuvanticity, and toxicity of intranasal amphiphile-antigen/adjuvant vaccines in a
‘dirty’ mouse model. Aim 3: Define mucosal vaccine kinetics that drive functional immune protection by
evaluating efficacy of intranasal amph-vaccines in challenge models of SARS-CoV-2. Our central hypothesis is
that i.n. amph-vaccines that exhibit enhanced mucosal uptake and persistence in NALT will better prime
functional protective immunity against respiratory pathogens (demonstrated across multiple mouse models) by
activating robust GC responses in NALT, generating a mucosal antibody response of greater magnitude, affinity,
and breadth than soluble or parenteral controls.document fetched 2026-08-02 08:24