title: Modifying the thermostability of inactivated influenza vaccines.
abstract: BACKGROUND
  Respiratory infections caused by influenza viruses spread rapidly, resulting in significant annual morbidity and mortality worldwide. Currently, the most effective public health measure against infection is immunisation with an influenza vaccine matching the relevant circulating influenza strains. Although a number of developments in terms of influenza vaccine production, safety and immunogenicity have been reported, limitations in our understanding of vaccine stability still exist. In this report we seek to identify compounds that increase influenza vaccine thermostability.
  
  
  METHODS
  We use plaque inhibition on confluent MDCK cells to identify compounds which inhibit the entry of various seed strain viruses. The effect of these compounds on vaccine thermal lability is evaluated through SRID analysis. The significance of these results is tested by a two-way analysis of variance (ANOVA) method.
  
  
  RESULTS
  We identify two compounds which selectively inhibit entry of different group I or group II influenza strains through prevention of the neutral-pH to low-pH conformational change of hemagglutinin. Compounds which were able to inhibit virus entry were also able to limit thermally induced potency loss in matched influenza vaccines. Furthermore, we demonstrate that this effect is independent of product formulation or the presence of multiple HA types.
  
  
  CONCLUSIONS
  This work provides further evidence for a link between HA conformational stability in the virus and thermostability of the corresponding vaccine preparation. It also suggests straightforward approaches to improve the stability and predictability of influenza vaccine preparations.
authors: Centre for Vaccine Evaluation, Biologics and Genetic Therapies Directorate, Health Canada, Ottawa, Canada.
authors: Alex
authors: A
authors: Bliu
authors: Michele
authors: M
authors: Lemieux
authors: Changgui
authors: C
authors: Li
authors: Xuguang
authors: X
authors: Li
authors: Junzhi
authors: J
authors: Wang
authors: Aaron
authors: A
authors: Farnsworth
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004345:Drug Industry; D004355:Drug Stability; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000737:chemistry / Q000276:immunology*; D006863:Hydrogen-Ion Concentration; D006873:Hydroquinones / Q000494:pharmacology; D007252:Influenza Vaccines / Q000737:chemistry / Q000276:immunology*; D061985:Madin Darby Canine Kidney Cells / Q000821:virology; D009975:Orthomyxoviridae / Q000187:drug effects / Q000472:pathogenicity; D010880:Piperidines / Q000494:pharmacology; D015164:Vaccines, Inactivated / Q000737:chemistry / Q000276:immunology*
chemical_list: C560737:3-fluoro-N-(2-(1-piperidinyl)ethyl)-5-(trifluoromethyl)benzamide; D001549:Benzamides; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D006873:Hydroquinones; D007252:Influenza Vaccines; D010880:Piperidines; D015164:Vaccines, Inactivated; C018855:2-tert-butylhydroquinone