title: A computationally optimized hemagglutinin virus-like particle vaccine elicits broadly reactive antibodies that protect nonhuman primates from H5N1 infection.
abstract: BACKGROUND
  Highly pathogenic H5N1 avian influenza viruses continue to spread via waterfowl, causing lethal infections in humans. Vaccines can prevent the morbidity and mortality associated with pandemic influenza isolates. Predicting the specific isolate that may emerge from the 10 different H5N1 clades is a tremendous challenge for vaccine design.
  
  
  METHODS
  In this study, we generated a synthetic hemagglutinin (HA) on the basis of a new method, computationally optimized broadly reactive antigen (COBRA), which uses worldwide sequencing and surveillance efforts that are specifically focused on sequences from H5N1 clade 2 human isolates.
  
  
  RESULTS
  Cynomolgus macaques vaccinated with COBRA clade 2 HA H5N1 virus-like particles (VLPs) had hemagglutination-inhibition antibody titers that recognized a broader number of representative isolates from divergent clades as compared to nonhuman primates vaccinated with clade 2.2 HA VLPs. Furthermore, all vaccinated animals were protected from A/Whooper Swan/Mongolia/244/2005 (WS/05) clade 2.2 challenge, with no virus detected in the nasal or tracheal washes. However, COBRA VLP-vaccinated nonhuman primates had reduced lung inflammation and pathologic effects as compared to those that received WS/05 VLP vaccines.
  
  
  CONCLUSIONS
  The COBRA clade 2 HA H5N1 VLP elicits broad humoral immunity against multiple H5N1 isolates from different clades. In addition, the COBRA VLP vaccine is more effective than a homologous vaccine against a highly pathogenic avian influenza virus challenge.
authors.affiliation: Center for Vaccine Research, University of Pittsburgh, Pennsylvania 15261, USA.
authors.forename: Brendan M
authors.initials: BM
authors.lastname: Giles
authors.forename: Corey J
authors.initials: CJ
authors.lastname: Crevar
authors.forename: Donald M
authors.initials: DM
authors.lastname: Carter
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: Bissel
authors.forename: Stacey
authors.initials: S
authors.lastname: Schultz-Cherry
authors.forename: Clayton A
authors.initials: CA
authors.lastname: Wiley
authors.forename: Ted M
authors.initials: TM
authors.lastname: Ross
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000914:Antibodies, Viral / Q000097:blood*; D000956:Antigens, Viral / Q000276:immunology; D002461:Cell Line, Transformed; D017076:Computer-Aided Design; D016384:Consensus Sequence; D004195:Disease Models, Animal; D006389:Hemagglutinins, Viral / Q000737:chemistry / Q000276:immunology*; D006801:Humans; D053124:Influenza A Virus, H5N1 Subtype / Q000276:immunology*; D007252:Influenza Vaccines / Q000276:immunology*; D007251:Influenza, Human / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D016013:Likelihood Functions; D008168:Lung / Q000821:virology; D008252:Macaca fascicularis; D008297:Male; D009976:Orthomyxoviridae Infections / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D010802:Phylogeny; D014611:Vaccination; D058425:Vaccines, Virus-Like Particle / Q000276:immunology
chemical_list: D000914:Antibodies, Viral; D000956:Antigens, Viral; D006389:Hemagglutinins, Viral; D007252:Influenza Vaccines; D058425:Vaccines, Virus-Like Particle