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.

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.

Figure 1.

Forest plots showing relative risks of medically-attended adverse events (A), serious adverse events (B), potential immune-mediated diseases (C) and adverse events of special interest (D), in participants who received A(H1N1)pdm09 or H5N1 AS03-adjuvanted vaccines in controlled trials (total vaccinated cohorts). Trials in which no endpoint of interest was reported are not included in the figure. RR, relative risk; CI, confidence interval.