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.

“World in motion” – emulsion adjuvants rising to meet the pandemic challenges

“…Evaluations of vaccine effectiveness have shown that adjuvanted influenza vaccines (including AS03 and MF59) are significantly more effective than non-adjuvanted vaccines in children 66 and other populations. Moreover, extensive evaluations have consistently shown that MF59 and AS03 have acceptable safety profiles 49 , 67 – 69 . Across study groups comprising different populations (children, adults, and older adults), the most frequently reported adverse events following vaccination with AS03- or MF59-adjuvanted vaccines were injection-site pain, fatigue, headache, and muscle aches.…”

Chimeric Hemagglutinin-Based Influenza Virus Vaccines Induce Protective Stalk-Specific Humoral Immunity and Cellular Responses in Mice

“…Importantly, the AS03- (and AS01-) adjuvanted cH8/1 and cH5/1 chimeric vaccines were tested in rabbits in good laboratory practice toxicity studies, and they were well tolerated at the administration site, with no unexpected local reactogenicity. In addition, AS03-adjuvanted H5N1 vaccine is approved by the U.S. Food and Drug Administration for use in humans from the age of 6 mo based on acceptable safety experience in more than 4000 persons; there is no reference to serious skin lesions in the vaccine’s prescribing information (35), nor was the risk of serious skin lesions increased in a pooled analysis of 22,521 adults who had received an AS03-adjuvanted H5N1 or H1N1pdm09 influenza or control vaccine that was performed to identify medically attended adverse events associated with receipt of AS03-containing in-fluenza vaccines (36). Taken together, this information further indicates that this finding is an isolated incident that is likely specific for the preclinical mouse model used in the T cell studies (23) and, therefore, of little relevance to the advanced development of these vaccines.…”

Facial paralysis and vaccinations: a vaccine adverse event reporting system review

“…Facial nerve palsy following vaccination is a very rare phenomenon, representing a total of 944 cases (0.26%) out of 358 769 reported adverse events. A meta-analysis of all safety data available from 28 completed clinical trials in patients receiving the influenza vaccine determined that the incidence rate of facial paresis and/or facial nerve (cranial nerve VII) paralysis per 100 000 person-years was 55.6 ( 19 ). In comparison, the annual incidence rate of Bell’s palsy, the most common aetiology of facial paralysis, is estimated in the literature to be between 13 and 53 cases per 100 000 person-years ( 4 , 18 ).…”