title: H1N1 influenza virus-like particles: physical degradation pathways and identification of stabilizers.
abstract: A simple and rapid approach to vaccine stabilization has been applied to a novel virus-like particle (VLP) that contains the primary influenza antigens (hemagglutinin and neuraminidase surface proteins). A complement of spectroscopic and light scattering techniques was used to characterize the physical stability of influenza VLPs as a function of temperature and pH, two pharmaceutically relevant stress factors. The resulting data set was mathematically converted into a three-color empirical phase diagram (EPD) that illustrates changes in physical state as a function of these stress factors. Conditions of temperature and pH corresponding to apparent phase boundaries in the EPD were then used to screen for inhibitors of VLP aggregation from a library of generally recognized as safe compounds. Several potent inhibitors of VLP aggregation were identified; of these, trehalose, sorbitol, and glycine were all found to exert significant stabilizing effects on viral protein tertiary structure and/or membrane integrity.
authors.affiliation: Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, Kansas 66047, USA.
authors.forename: Julian
authors.initials: J
authors.lastname: Kissmann
authors.forename: Sangeeta B
authors.initials: SB
authors.lastname: Joshi
authors.forename: Joel R
authors.initials: JR
authors.lastname: Haynes
authors.forename: Leslie
authors.initials: L
authors.lastname: Dokken
authors.forename: Charles
authors.initials: C
authors.lastname: Richardson
authors.forename: C Russell
authors.initials: CR
authors.lastname: Middaugh
mesh_terms: D002942:Circular Dichroism; D005079:Excipients / Q000737:chemistry*; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000737:chemistry / Q000276:immunology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D053118:Influenza A Virus, H1N1 Subtype / Q000737:chemistry / Q000201:enzymology / Q000276:immunology*; D007252:Influenza Vaccines / Q000737:chemistry* / Q000276:immunology*; D007251:Influenza, Human / Q000517:prevention & control*; D008027:Light; D009439:Neuraminidase / Q000737:chemistry / Q000276:immunology; D044367:Phase Transition; D012542:Scattering, Radiation; D013050:Spectrometry, Fluorescence; D013696:Temperature; D014771:Virion / Q000737:chemistry / Q000276:immunology*
chemical_list: D005079:Excipients; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D007252:Influenza Vaccines; D009439:Neuraminidase