title: Immunogenicity and safety of an AS03-adjuvanted H7N1 vaccine in healthy adults: A phase I/II, observer-blind, randomized, controlled trial.
abstract: H7 influenza strains have pandemic potential. AS03-adjuvanted H7N1 A/mallard/Netherlands/12/2000 split-virion vaccine formulations were evaluated as model H7-subtype vaccine and tested after H7N9 emerged in China, and caused severe human disease with high mortality.
  
  
  
  In this phase I/II, observer-blind, randomized trial in US and Canada, 420 healthy adults (21-64years) were randomized to receive 1 of 4 H7N1 vaccine formulations (3.75 or 7.5μg hemagglutinin adjuvanted with either AS03Aor AS03B), 15μg unadjuvanted H7N1 hemagglutinin, or saline placebo, given as 2-dose series. Immunogenicity was assessed using hemagglutination-inhibition (HI) and microneutralization (MN) assays, at day 42 (21days post-dose 2), month 6, and month 12 (HI only) for the per-protocol cohorts (398, 379 and 368 participants, respectively). Safety is reported up to month 12.
  
  
  
  Beneficial AS03 adjuvant effect was demonstrated. Committee for Medical Products for Human Use, and Center for Biologics Evaluation and Research (CBER) criteria were met for all adjuvanted formulations at day 42 (H7N1 HI assay); seroprotection (SPR) and seroconversion rates (SCR) were 88.5-94.8%, mean geometric increase (MGI) 19.2-34.9, and geometric mean titers (GMT) 98.3-180.7. Unadjuvanted H7N1 vaccine did not meet CBER criteria. In adjuvanted groups, antibody titers decreased over time; month 12 SPRs and GMTs were low (2.0-18.8% and 8.1-12.2). MN antibodies showed similar kinetics, with titers persisting at higher range than HI at month 6. All adjuvanted groups showed cross-reactivity against H7N9, with HI responses similar to H7N1. The most frequent solicited symptom in adjuvanted groups was injection site pain (71.2-86.7%); grade 3 solicited symptoms were infrequent. Nine participants reported 17 serious adverse events; none were considered causally related to vaccination.
  
  
  
  Adjuvanted H7N1 vaccine formulations had an acceptable safety profile and induced an antibody response after 2 doses with cross-reactivity to H7N9. ClinicalTrials.gov: NCT01934127.
authors.affiliation: GSK, 1250 South Collegeville Road, Collegeville, PA 19426, USA. Electronic address: Anu.2.Madan@gsk.com.
authors.forename: Anuradha
authors.initials: A
authors.lastname: Madan
authors.affiliation: Colchester Research Group, 68 Robie Street, Truro, Nova Scotia B2N 1L2, Canada.
authors.forename: Murdo
authors.initials: M
authors.lastname: Ferguson
authors.affiliation: Miami Research Associates, 6141 Sunset Drive Suite 501, Miami 33143, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Sheldon
authors.affiliation: Clinical Research Atlanta, 175 Country Club Dr. Ste A, Stockbridge 30281, USA.
authors.forename: Nathan
authors.initials: N
authors.lastname: Segall
authors.affiliation: Benchmark Research, 1015 East 32nd Street, Suite 309, Austin, TX 78705, USA.
authors.forename: Laurence
authors.initials: L
authors.lastname: Chu
authors.affiliation: Manna Research, 2291 Kipling Avenue Suite 117B, Toronto, Ontario M9W 4L6, Canada. Electronic address: azhar.toma@mannaresearch.com.
authors.forename: Azhar
authors.initials: A
authors.lastname: Toma
authors.affiliation: Medicor Research Inc, 202-1280 Lasalle Blvd, Sudbury, Ontario P3E 1H5, Canada.
authors.forename: Paul
authors.initials: P
authors.lastname: Rheault
authors.affiliation: GSK, 20 Avenue Fleming, 1300 Wavre, Belgium.
authors.forename: Damien
authors.initials: D
authors.lastname: Friel
authors.affiliation: GSK Pharmaceuticals Ltd., 5 Embassy Links, SRT Road, Bangalore, India.
authors.forename: Jyoti
authors.initials: J
authors.lastname: Soni
authors.affiliation: GSK, 2301 Renaissance Blvd, King of Prussia, PA 19406-2772, USA. Electronic address: ping.li4@pfizer.com.
authors.forename: Ping
authors.initials: P
authors.lastname: Li
authors.affiliation: GSK, 14200 Shady Grove Road, Rockville, MD 20850, USA.
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Innis
authors.affiliation: GSK, 2301 Renaissance Blvd, King of Prussia, PA 19406-2772, USA.
authors.forename: Anne
authors.initials: A
authors.lastname: Schuind
mesh_terms: D056704:Adaptive Immunity; D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000328:Adult; D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D002170:Canada; D004338:Drug Combinations; D064420:Drug-Related Side Effects and Adverse Reactions / Q000453:epidemiology / Q000473:pathology; D005260:Female; D064368:Healthy Volunteers; D006385:Hemagglutination Inhibition Tests; D006801:Humans; D057916:Influenza A Virus, H7N1 Subtype / Q000276:immunology*; D007252:Influenza Vaccines / Q000008:administration & dosage / Q000009:adverse effects* / Q000276:immunology*; D007251:Influenza, Human / Q000517:prevention & control*; D008297:Male; D008875:Middle Aged; D009500:Neutralization Tests; D010919:Placebos / Q000008:administration & dosage; D011136:Polysorbates / Q000008:administration & dosage*; D016037:Single-Blind Method; D013185:Squalene / Q000008:administration & dosage*; D014481:United States; D015164:Vaccines, Inactivated / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology; D055815:Young Adult; D024502:alpha-Tocopherol / Q000008:administration & dosage*
chemical_list: D000276:Adjuvants, Immunologic; D000914:Antibodies, Viral; D004338:Drug Combinations; D007252:Influenza Vaccines; D010919:Placebos; D011136:Polysorbates; D015164:Vaccines, Inactivated; D013185:Squalene; C550253:AS03 adjuvant; D024502:alpha-Tocopherol
keywords: AS03 adjuvant; H7 influenza vaccine; H7N1; H7N9; Pandemic flu