title: Serological responses to an avian influenza A/H7N9 vaccine mixed at the point-of-use with MF59 adjuvant: a randomized clinical trial.
abstract: OBJECTIVE
  Human infections with avian influenza A/H7N9 have resulted in high morbidity and mortality in China.
  
  
  OBJECTIVE
  To compare safety and immunogenicity of different doses of influenza A/Shanghai/2/13 (H7N9) vaccine mixed with or without the MF59 adjuvant.
  
  
  METHODS
  Multicenter, randomized, double-blind, phase 2 trial at 4 US sites enrolled 700 adults aged 19 to 64 years beginning in September 2013; 6-month follow-up was completed in May 2014.
  
  
  METHODS
  The H7N9 inactivated virus vaccine was administered intramuscularly on days 0 and 21 at nominal doses of 3.75, 7.5, 15, or 45 µg of hemagglutinin (actual doses approximately 50% higher) with or without the MF59 adjuvant. A total 99, 100, or 101 participants were randomized to each group (7 groups; N = 700).
  
  
  METHODS
  Proportions achieving day 42 antibody titer of 40 or greater or seroconversion (a minimum 4-fold increase to titer ≥40) with the hemagglutination inhibition assay; vaccine-related serious adverse events through month 13; and solicited postvaccination symptoms through day 7.
  
  
  RESULTS
  Hemagglutination inhibition antibodies were minimal after participants received an unadjuvanted vaccine. After receiving 2 doses of H7N9 vaccine at a dosage of 3.75 µg plus the MF59 adjuvant, day 42 seroconversion occurred in 58 participants (59%; 95% CI, 48%-68%). The peak seroconversion occurred at day 29 in 62 participants (62%; 95% CI, 52%-72%). The day 42 geometric mean titer was 33.0 (95% CI, 24.7-44.1). Higher antigen doses were not associated with increased response. For the neutralizing antibody assays, after receiving 3.75 µg of H7N9 vaccine plus the MF59 adjuvant, day 42 seroconversion occurred in 81 participants (82%; 95% CI, 73%-89%). The day 42 geometric mean titer was 81.4 (95% CI, 66.6-99.5). There was no statistically significant difference in day 42 hemagglutination inhibition seroconversion after mixing adjuvant with either the first or both 15 µg doses (n = 34 [35%; 95% CI, 25%-45%] vs n = 47 [47%; 95% CI, 37%-58%], respectively; P = .10). Recent receipt of seasonal influenza vaccination and older age were associated with attenuated response. No vaccine-related serious adverse events occurred. Solicited postvaccination symptoms were generally mild with more local symptoms seen in participants who received the adjuvant.
  
  
  CONCLUSIONS
  Point-of-use mixing and administration of 2 doses of H7N9 vaccine at the lowest tested antigen dose with MF59 adjuvant produced seroconversion in 59% of participants. Although these findings indicate potential value in this approach, the study is limited by the absence of antibody data beyond 42 days and the absence of clinical outcomes.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT01938742.
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Mulligan
authors.affiliation: Cincinnati Children's Hospital and Medical Center, University of Cincinnati, Cincinnati, Ohio.
authors.forename: David I
authors.initials: DI
authors.lastname: Bernstein
authors.affiliation: University of Iowa, Iowa City4Iowa City VA Healthcare System, Iowa City, Iowa.
authors.forename: Patricia
authors.initials: P
authors.lastname: Winokur
authors.affiliation: University of Texas Medical Branch, Galveston.
authors.forename: Richard
authors.initials: R
authors.lastname: Rupp
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia6Division of Pediatric Infectious Diseases, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia.
authors.forename: Evan
authors.initials: E
authors.lastname: Anderson
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia.
authors.forename: Nadine
authors.initials: N
authors.lastname: Rouphael
authors.affiliation: Cincinnati Children's Hospital and Medical Center, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Michelle
authors.initials: M
authors.lastname: Dickey
authors.affiliation: University of Iowa, Iowa City4Iowa City VA Healthcare System, Iowa City, Iowa.
authors.forename: Jack T
authors.initials: JT
authors.lastname: Stapleton
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia.
authors.forename: Srilatha
authors.initials: S
authors.lastname: Edupuganti
authors.affiliation: Division of Pediatric Infectious Diseases, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia.
authors.forename: Paul
authors.initials: P
authors.lastname: Spearman
authors.affiliation: University of Iowa, Iowa City4Iowa City VA Healthcare System, Iowa City, Iowa.
authors.forename: Dilek
authors.initials: D
authors.lastname: Ince
authors.affiliation: Southern Research Institute, Birmingham, Alabama.
authors.forename: Diana L
authors.initials: DL
authors.lastname: Noah
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*; D000328:Adult; D000914:Antibodies, Viral; D000917:Antibody Formation; D000956:Antigens, Viral; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D064766:Influenza A Virus, H7N9 Subtype; D007252:Influenza Vaccines / Q000008:administration & dosage* / 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* / Q000276:immunology; D014611:Vaccination / Q000379:methods; D055815:Young Adult
chemical_list: D000276:Adjuvants, Immunologic; D000914:Antibodies, Viral; D000956:Antigens, Viral; D007252:Influenza Vaccines; C089950:MF59 oil emulsion; D011136:Polysorbates; D013185:Squalene