title: Effect of Varying Doses of a Monovalent H7N9 Influenza Vaccine With and Without AS03 and MF59 Adjuvants on Immune Response: A Randomized Clinical Trial.
abstract: OBJECTIVE
  Human infections with the avian influenza A(H7N9) virus were first reported in China in 2013 and continue to occur. Hemagglutinin H7 administered alone is a poor immunogen necessitating evaluation of adjuvanted H7N9 vaccines.
  
  
  OBJECTIVE
  To evaluate the immunogenicity and safety of an inactivated H7N9 vaccine with and without AS03 adjuvant, as well as mixed vaccine schedules that included sequential administration of AS03- and MF59-containing formulations and of adjuvanted and unadjuvanted formulations.
  
  
  METHODS
  Double-blind, phase 2 trial at 5 US sites enrolled 980 adults aged 19 through 64 years from September 2013 through November 2013; safety follow-up was completed in January 2015.
  
  
  METHODS
  The H7N9 vaccine was given on days 0 and 21 at nominal doses of 3.75 µg, 7.5 µg, 15 µg, and 45 µg of hemagglutinin with or without AS03 or MF59 adjuvant mixed on site.
  
  
  METHODS
  Proportions achieving a hemagglutination inhibition antibody (HIA) titer of 40 or higher at 21 days after the second vaccination; vaccine-related serious adverse events through 12 months after the first vaccination; and solicited signs and symptoms after vaccination through day 7.
  
  
  RESULTS
  Two doses of vaccine were required to induce detectable antibody titers in most participants. After 2 doses of an H7N9 formulation containing 15 µg of hemagglutinin given without adjuvant, with AS03 adjuvant, or with MF59 adjuvant, the proportion achieving an HIA titer of 40 or higher was 2% (95% CI, 0%-7%) without adjuvant (n = 94), 84% (95% CI, 76%-91%) with AS03 adjuvant (n = 96), and 57% (95% CI, 47%-68%) with MF59 adjuvant (n = 92) (P < .001 for comparison of the AS03 and MF59 schedules). The 2 schedules alternating AS03-and MF59-adjuvanted formulations led to lower geometric mean titers (GMTs) of (41.5 [95% CI, 31.7-54.4]; n = 92) and (58.6 [95% CI, 44.3-77.6]; n = 96) than the group induced by 2 AS03-adjuvanted formulations (n = 96) (103.4 [95% CI, 78.7-135.9]; P < .001) but higher GMTs than 2 doses of MF59-adjuvanted formulation (n = 94) (29.0 [95% CI, 22.4-37.6]; P < .001).
  
  
  CONCLUSIONS
  The AS03 and MF59 adjuvants augmented the immune responses to 2 doses of an inactivated H7N9 influenza vaccine, with AS03-adjuvanted formulations inducing the highest titers. This study of 2 adjuvants used in influenza vaccine formulations with adjuvant mixed on site provides immunogenicity information that may be informative to influenza pandemic preparedness programs.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT01942265.
authors.affiliation: Group Health Research Institute, Seattle, Washington.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Jackson
authors.affiliation: Division of Infectious Disease and Tropical Pediatrics, Department of Pediatrics, Center for Vaccine Development, University of Maryland School of Medicine, Baltimore.
authors.forename: James D
authors.initials: JD
authors.lastname: Campbell
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: Vanderbilt Vaccine Research Program, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Edwards
authors.affiliation: Departments of Molecular Virology and Microbiology and Medicine, Baylor College of Medicine, Houston, Texas.
authors.forename: Wendy A
authors.initials: WA
authors.lastname: Keitel
authors.affiliation: Division of Infectious Disease and Tropical Pediatrics, Department of Pediatrics, Center for Vaccine Development, University of Maryland School of Medicine, Baltimore.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Kotloff
authors.affiliation: Division of Infectious Disease and Tropical Pediatrics, Department of Pediatrics, Center for Vaccine Development, University of Maryland School of Medicine, Baltimore.
authors.forename: Andrea A
authors.initials: AA
authors.lastname: Berry
authors.affiliation: Division of Infectious Diseases, Allergy, and Immunology, Saint Louis University School of Medicine, St Louis, Missouri.
authors.forename: Irene
authors.initials: I
authors.lastname: Graham
authors.affiliation: Departments of Molecular Virology and Microbiology and Medicine, Baylor College of Medicine, Houston, Texas.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Atmar
authors.affiliation: Vanderbilt Vaccine Research Program, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: C Buddy
authors.initials: CB
authors.lastname: Creech
authors.affiliation: Vanderbilt Vaccine Research Program, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Isaac P
authors.initials: IP
authors.lastname: Thomsen
authors.affiliation: Departments of Molecular Virology and Microbiology and Medicine, Baylor College of Medicine, Houston, Texas.
authors.forename: Shital M
authors.initials: SM
authors.lastname: Patel
authors.affiliation: Departments of Molecular Virology and Microbiology and Medicine, Baylor College of Medicine, Houston, Texas.
authors.forename: Andres F
authors.initials: AF
authors.lastname: Gutierrez
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: Departments of Molecular Virology and Microbiology and Medicine, Baylor College of Medicine, Houston, Texas.
authors.forename: Hana M
authors.initials: HM
authors.lastname: El Sahly
authors.affiliation: The EMMES Corporation, Rockville, Maryland.
authors.forename: Heather
authors.initials: H
authors.lastname: Hill
authors.affiliation: Southern Research Institute, Birmingham, Alabama.
authors.forename: Diana L
authors.initials: DL
authors.lastname: Noah
authors.affiliation: The EMMES Corporation, Rockville, Maryland.
authors.forename: Abbie R
authors.initials: AR
authors.lastname: Bellamy
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000328:Adult; D000367:Age Factors; D000914:Antibodies, Viral / Q000097:blood; D004311:Double-Blind Method; D004338:Drug Combinations; D005260:Female; D006385:Hemagglutination Inhibition Tests; D006387:Hemagglutination, Viral / Q000276:immunology; D006801:Humans; D064766:Influenza A Virus, H7N9 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; D024502:alpha-Tocopherol / Q000008:administration & dosage
chemical_list: D000276:Adjuvants, Immunologic; D000914:Antibodies, Viral; D004338:Drug Combinations; D007252:Influenza Vaccines; C089950:MF59 oil emulsion; D011136:Polysorbates; D013185:Squalene; C550253:AS03 adjuvant; D024502:alpha-Tocopherol