title: Highly increased levels of IgE antibodies to vaccine components in children with influenza vaccine-associated anaphylaxis.
abstract: BACKGROUND
  Influenza vaccines produced in embryonated eggs might pose a risk to patients with egg allergy. However, patients experiencing influenza vaccine-associated anaphylaxis (IVA) do not always have egg allergy. In the 2011-2012 season, an unusually high incidence of IVA was reported in Japan.
  
  
  OBJECTIVE
  We sought to identify the cause of the increase in anaphylactic events in 2011-2012 in Japan.
  
  
  METHODS
  We collected blood specimens from patients with IVA from all areas of Japan. We analyzed 19 patients with confirmed IVA and 25 age-matched control subjects, including 10 with egg allergy who had no adverse events after corresponding vaccination. ELISA was used to measure specific IgE levels to the trivalent vaccines of several manufacturers and hemagglutinin proteins derived from both egg and cell cultures. Antigen-induced basophil activation was evaluated by measuring CD203c expression by means of flow cytometry. Vaccine excipients were also examined for effects on CD203c expression.
  
  
  RESULTS
  None of the patients with IVA had severe egg allergy. Levels of specific IgE antibodies to influenza vaccine antigens, whole-vaccine products from different manufacturers, and hemagglutinin proteins (A H1, H3, and B) derived from both egg and cell cultures were significantly increased in patients with IVA compared with those in control subjects. Influenza vaccine-induced CD203c expression in basophils was also highly enhanced in patients with IVA but not in control subjects. Because IVA was most frequent in patients who received 2-phenoxyethanol (2-PE)-containing vaccine, the effect of this preservative on basophil activation was examined, and the activation was slightly enhanced by 2-PE but not thimerosal.
  
  
  CONCLUSIONS
  The 2011-2012 IVA spike in Japan was caused by specific IgE antibodies to influenza vaccine components. Excipients could not be implicated, except for a modest effect of 2-PE.
authors.affiliation: Allergy Center, Mie National Hospital, Tsu, Japan.
authors.forename: Mizuho
authors.initials: M
authors.lastname: Nagao
authors.affiliation: Allergy Center, Mie National Hospital, Tsu, Japan. Electronic address: fujisawa@mie-m.hosp.go.jp.
authors.forename: Takao
authors.initials: T
authors.lastname: Fujisawa
authors.affiliation: Infectious Disease Center, Mie National Hospital, Tsu, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Ihara
authors.affiliation: Chemo-Sero-Therapeutic Research Institute (Kaketsuken), Kumamoto, Japan.
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Kino
mesh_terms: D000707:Anaphylaxis / Q000276:immunology*; D000918:Antibody Specificity / Q000276:immunology; D001491:Basophils / Q000276:immunology / Q000378:metabolism; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D021181:Egg Hypersensitivity / Q000276:immunology; D005260:Female; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000276:immunology; D006801:Humans; D007073:Immunoglobulin E / Q000097:blood / Q000276:immunology*; D007252:Influenza Vaccines / Q000009:adverse effects* / Q000276:immunology*; D007564:Japan; D008297:Male; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D011755:Pyrophosphatases / Q000378:metabolism; D012307:Risk Factors; D014611:Vaccination
chemical_list: C427944:ENPP3 protein, human; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D007252:Influenza Vaccines; D007073:Immunoglobulin E; D010727:Phosphoric Diester Hydrolases; D011755:Pyrophosphatases
keywords: Anaphylaxis; IgE; basophil activation; hemagglutinin; influenza vaccine