title: Safety of AS03-adjuvanted inactivated split virion A(H1N1)pdm09 and H5N1 influenza virus vaccines administered to adults: pooled analysis of 28 clinical trials.
abstract: Clinical trials have shown that AS03-adjuvanted H5N1 and A(H1N1)pdm09 vaccines are highly immunogenic, although with an increased reactogenicity profile relative to non-adjuvanted vaccines in terms of the incidence of common injection site and systemic adverse events (AEs). We evaluated pooled safety data from 22,521 adults who had received an AS03-adjuvanted H5N1 or A(H1N1)pdm09 influenza or control vaccine with the purpose to identify medically-attended AEs (MAEs), including subsets of serious AEs (SAEs), potentially immune-mediated diseases (pIMDs), and AEs of special interest (AESI), and to explore a potential association of these AEs with the administration of an AS03-adjuvanted influenza vaccine. For participants who had received an AS03-adjuvanted vaccine, the relative risks (RRs) for experiencing a MAE or a SAE compared to control group (participants who had received a non-adjuvanted vaccine or saline placebo) were 1.0 (95% confidence interval [CI]: 0.9; 1.1) and 1.1 (95% CI: 0.9; 1.4), respectively. The overall RRs for experiencing an AESI or a pIMD (AS03-adjuvanted vaccine/control) were 1.2 (95% CI: 0.9; 1.6) and 1.7 (95% CI: 0.8; 3.8), respectively. Thirty-8 participants in the AS03-adjuvanted vaccine group had a pIMD reported after vaccine administration, yielding an incidence rate (IR) of 351.9 (95% CI: 249.1; 483.1) per 100,000 person-years. The estimated IRs in the AS03-adjuvanted vaccine group were greater than the literature reported rates for: facial paresis/VIIth nerve paralysis, celiac disease, thrombocytopenia and ulcerative colitis. These results do not support an association between AS03-adjuvanted H5N1 and A(H1N1)pdm09 vaccines and the AEs collected in the trials included in the analysis.
authors.affiliation: a GlaxoSmithKline Vaccines ; Rixensart , Belgium.
authors.forename: David W
authors.initials: DW
authors.lastname: Vaughn
authors.forename: Harry
authors.initials: H
authors.lastname: Seifert
authors.forename: Anne
authors.initials: A
authors.lastname: Hepburn
authors.forename: Walthere
authors.initials: W
authors.lastname: Dewe
authors.forename: Ping
authors.initials: P
authors.lastname: Li
authors.forename: Mamadou
authors.initials: M
authors.lastname: Drame
authors.forename: Catherine
authors.initials: C
authors.lastname: Cohet
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Innis
authors.forename: Louis F
authors.initials: LF
authors.lastname: Fries
mesh_terms: D000276:Adjuvants, Immunologic / Q000009:adverse effects* / Q000627:therapeutic use; D000293:Adolescent; D000328:Adult; D000914:Antibodies, Viral / Q000276:immunology; D004338:Drug Combinations; D005260:Female; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology*; D053124:Influenza A Virus, H5N1 Subtype / Q000276:immunology*; D007252:Influenza Vaccines / Q000009:adverse effects / Q000627:therapeutic use*; D007251:Influenza, Human / Q000276:immunology / Q000517:prevention & control / Q000821:virology; D008297:Male; D008875:Middle Aged; D011136:Polysorbates / Q000009:adverse effects* / Q000627:therapeutic use; D012306:Risk; D013185:Squalene / Q000009:adverse effects* / Q000627:therapeutic use; D014611:Vaccination; D055815:Young Adult; D024502:alpha-Tocopherol / Q000009:adverse effects* / Q000627:therapeutic use
chemical_list: D000276:Adjuvants, Immunologic; D000914:Antibodies, Viral; D004338:Drug Combinations; D007252:Influenza Vaccines; D011136:Polysorbates; D013185:Squalene; C550253:AS03 adjuvant; D024502:alpha-Tocopherol
keywords: AE; Center for Biologics Evaluation and Research; CHMP; Committee for Medicinal Products for Human Use; MedDRA; Good Clinical Practice; CBER; Medical Dictionary for Regulatory Activities; PT; adverse event of special interest; MAE; adverse event; pIMD; confidence interval; RR; incidence rate; GCP; medically-attended adverse event; SAE; new onset chronic disease; CI; potential immune-mediated disease; AESI; preferred term; relative risk; SD; safety, potential immune-mediated disease, A(H1N1)pdm09 vaccine, H5N1 vaccine, influenza A(H5N1), pandemic influenza A(H1N1), pooled analysis; serious adverse event; NOCD; standard deviation; IR