title: Immunogenicity of avian influenza A/Anhui/01/2005(H5N1) vaccine with MF59 adjuvant: a randomized clinical trial.
abstract: OBJECTIVE
  The need to respond quickly to potential influenza pandemics is important. Immunologic priming (initial presentation of an antigen to allow antibody responses on revaccination) with vaccine directed toward an older avian influenza H5 strain might lead to secondary antibody responses to a single dose of more current H5 avian influenza vaccine.
  
  
  OBJECTIVE
  To assess priming with the older avian influenza A/Vietnam/1203/2004(H5N1) (Vietnam) vaccine and to conduct dose-response studies with vaccine directed against the more contemporary H5N1 avian influenza virus, influenza A/Anhui/01/2005 (Anhui).
  
  
  METHODS
  Multicenter US randomized clinical trial beginning in June 2010 with follow-up continuing through October 2011 enrolling 72 healthy adults who were vaccinated 1 year previously with the Vietnam vaccine and 565 vaccine-naive adults.
  
  
  METHODS
  Participants who were previously vaccinated with 90 µg of unadjuvanted Vietnam vaccine were randomly assigned to receive 3.75 µg of avian influenza Anhui vaccine with or without MF59 adjuvant, stratified by 1 vs 2 previous doses (1 dose: n = 18 with MF59 and n = 17 without; 2 doses: n = 19 with MF59 and n = 18 without). Vaccine-naive individuals were randomly assigned to receive Ahnui vaccine with or without MF59 adjuvant in 1 of 5 doses (3.75 µg [n = 55 with MF59 and n = 59 without], 7.5 µg [n = 51 with MF59 and n = 57 without], 15 µg [n = 48 with MF59 and n = 44 without], 45 µg [n = 47 with MF59 and n = 47 without], or 90 µg [n = 57 without adjuvant]) or placebo (n = 100) given at days 0 and 28.
  
  
  METHODS
  The primary immunogenicity outcome was hemagglutination inhibition assay (HAI) titer against each vaccine antigen 1 month (day 28) and 6 months (day 180) after last vaccination. The primary safety outcomes were local and systemic adverse events on days 0 to 7 after each vaccination and serious adverse events.
  
  
  RESULTS
  Previously vaccinated participants manifested secondary antibody responses after receipt of low-dose Anhui vaccine ("boosting"); by day 28, 21% to 50% developed HAI responses of 1:40 or greater. Use of adjuvant was not associated with increased HAI responses. Among vaccine-naive participants (n = 565), the optimum dose was 7.5 µg of antigen with adjuvant (geometric mean titer [GMT], 63.3; 95% CI, 43.0-93.1). The greatest response to unadjuvanted antigen was seen at the highest dose, 90 µg (GMT, 28.5; 95% CI, 19.7-41.2). Local or systemic reactions occurred, respectively, in 40 (78%) and 25 (49%) of 51 participants who received 7.5 µg plus adjuvant vs 50 (88%) and 29 (51%) of 57 who received 90 µg of unadjuvanted vaccine. In general, antibodies were short-lived, and by day 180, HAI titers had decreased to less than 1:20 in all treatment groups.
  
  
  CONCLUSIONS
  Previous receipt of a single dose of influenza A(H5N1) Vietnam vaccine was associated with sufficient immunologic priming to facilitate antibody response to a different H5N1 antigen using low-dose Anhui (booster) vaccine. In participants who had not previously received H5 vaccine, low-dose Anhui vaccine plus adjuvant was more immunogenic compared with higher doses of unadjuvanted vaccine.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT00680069.
authors.affiliation: Division of Infectious Diseases, Allergy, and Immunology, Saint Louis University School of Medicine, St Louis, Missouri.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Belshe
authors.affiliation: Division of Infectious Diseases, Allergy, and Immunology, Saint Louis University School of Medicine, St Louis, Missouri.
authors.forename: Sharon E
authors.initials: SE
authors.lastname: Frey
authors.affiliation: Division of Infectious Diseases, Allergy, and Immunology, Saint Louis University School of Medicine, St Louis, Missouri.
authors.forename: Irene L
authors.initials: IL
authors.lastname: Graham
authors.affiliation: Division of Infectious Diseases, Allergy, and Immunology, Saint Louis University School of Medicine, St Louis, Missouri.
authors.forename: Edwin L
authors.initials: EL
authors.lastname: Anderson
authors.affiliation: Group Health Research Institute, Seattle, Washington.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Jackson
authors.affiliation: Emory Children's Center, Atlanta, Georgia.
authors.forename: Paul
authors.initials: P
authors.lastname: Spearman
authors.affiliation: Hope Clinic of Emory University, Atlanta, Georgia.
authors.forename: Srilatha
authors.initials: S
authors.lastname: Edupuganti
authors.affiliation: Hope Clinic of Emory University, Atlanta, Georgia.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Mulligan
authors.affiliation: Hope Clinic of Emory University, Atlanta, Georgia.
authors.forename: Nadine
authors.initials: N
authors.lastname: Rouphael
authors.affiliation: University of Iowa Hospitals and Clinics, Iowa City.
authors.forename: Patricia
authors.initials: P
authors.lastname: Winokur
authors.affiliation: Duke Clinical Vaccine Unit, Duke University School of Medicine, Durham, North Carolina.
authors.forename: Rowena J
authors.initials: RJ
authors.lastname: Dolor
authors.affiliation: Duke Clinical Vaccine Unit, Duke University School of Medicine, Durham, North Carolina.
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Woods
authors.affiliation: Duke Clinical Vaccine Unit, Duke University School of Medicine, Durham, North Carolina.
authors.forename: Emmanuel B
authors.initials: EB
authors.lastname: Walter
authors.affiliation: Center for Vaccine Development, University of Maryland School of Medicine, Baltimore.
authors.forename: Wilbur H
authors.initials: WH
authors.lastname: Chen
authors.affiliation: University of Texas Medical Branch, Galveston.
authors.forename: Christine
authors.initials: C
authors.lastname: Turley
authors.affiliation: Vanderbilt Vaccine Research Program, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Edwards
authors.affiliation: Vanderbilt Vaccine Research Program, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: C Buddy
authors.initials: CB
authors.lastname: Creech
authors.affiliation: EMMES Corporation, Rockville, Maryland.
authors.forename: Heather
authors.initials: H
authors.lastname: Hill
authors.affiliation: EMMES Corporation, Rockville, Maryland.
authors.forename: Abbie R
authors.initials: AR
authors.lastname: Bellamy
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D000917:Antibody Formation; D004305:Dose-Response Relationship, Drug; D005260:Female; D006385:Hemagglutination Inhibition Tests; D006801:Humans; D007117:Immunization, Secondary; D053124:Influenza A Virus, H5N1 Subtype; D007252:Influenza Vaccines / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology; D007251:Influenza, Human / Q000276:immunology / Q000517:prevention & control*; D008297:Male; D008875:Middle Aged; D011136:Polysorbates / Q000008:administration & dosage; D013185:Squalene / Q000008:administration & dosage; D014611:Vaccination / Q000379:methods; D055815:Young Adult
chemical_list: D000276:Adjuvants, Immunologic; D007252:Influenza Vaccines; C089950:MF59 oil emulsion; D011136:Polysorbates; D013185:Squalene