Sequential release of influenza hemagglutinin variants using liposomes and polymers with programmable release kinetics.
Abstract
Vaccination is one of the most cost-effective measures to save lives, and has been responsible for the complete, or near complete, eradication of several infectious diseases. Conventional vaccine approaches are less effective for providing protection against multiple variant antigens (Ags), particularly when administered in a single dose. In this multidisciplinary application, that combines immunologists, chemists, pharmaceutical and biochemical engineers, we propose to develop a single-shot formulation platform, using influenza hemagglutinin (HA) variants (H1, H5, H7) as a model Ag, followed by filovirus glycoprotein (GP) variant Ags from Marburg and Ebola (species Zaire and Sudan) viruses. Each variant will be delivered in a different delivery vehicle designed for non-synchronous Ag-release in vivo. These vehicles will comprise lipid-based nanoparticles, protein-based nanoparticles, and microspheres, and modified with toll-like receptor (TLR) 7/8-agonist for increased adjuvanticity. Antibody (Ab) crossreactivity will be evaluated on HA and GP variant protein microarrays, and affinity maturation confirmed by affinity measurements in sera, and by Ab V-gene sequencing. Cross-reactivity of anti-HA antibodies will also be evaluated in vivo for protection against challenge with heterologous influenza strains. This platform (Fig. 1), we call Affinity Maturation of Antibody by Non-synchronous Delivery of Antigen (AMANDA), can be applied to other variant pathogens of relevance to the warfighter.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- HDTRA11810036
Entities
People
- David Davies
Organizations
- Defense Threat Reduction Agency
- University of California, Irvine