Phase II, randomized, open, controlled study of AS03‐adjuvanted H5N1 pre‐pandemic influenza vaccine in children aged 3 to 9 years: follow‐up of safety and immunogenicity persistence at 24 months post‐vaccination

Abstract

BackgroundAn AS03-adjuvanted H5N1 influenza vaccine elicited broad and persistent immune responses with an acceptable safety profile up to 6 months following the first vaccination in children aged 3–9 years.MethodsIn this follow-up of the Phase II study, we report immunogenicity persistence and safety at 24 months post-vaccination in children aged 3–9 years. The randomized, open-label study assessed two doses of H5N1 A/Vietnam/1194/2004 influenza vaccine (1·9 μg or 3·75 μg hemagglutinin antigen) formulated with AS03A or AS03B (11·89 mg or 5·93 mg tocopherol, respectively). Control groups received seasonal trivalent influenza vaccine. Safety was assessed prospectively and included potential immune-mediated diseases (pIMDs). Immunogenicity was assessed by hemagglutination-inhibition assay 12 and 24 months after vaccination; cross-reactivity and cell-mediated responses were also assessed. (NCT00502593).ResultsThe safety population included 405 children. Over 24 months, five events fulfilled the criteria for pIMDs, of which four occurred in H5N1 vaccine recipients, including uveitis (n = 1) and autoimmune hepatitis (n = 1), which were considered to be vaccine-related. Overall, safety profiles of the vaccines were clinically acceptable. Humoral immune responses at 12 and 24 months were reduced versus those observed after the second dose of vaccine, although still within the range of those observed after the first dose. Persistence of cell-mediated immunity was strong, and CD4+ T cells with a TH1 profile were observed.ConclusionsTwo doses of an AS03-adjuvanted H5N1 influenza vaccine in children showed low but persistent humoral immune responses and a strong persistence of cell-mediated immunity, with clinically acceptable safety profiles up to 24 months following first vaccination.

Reactogenicity and safety of AS03B-adjuvanted H5N1 influenza vaccine in children: an open-label, one-way, crossover trial

“…children in Year 2 were about a year older than those in Year 1, and the Year 2 crossover study included eligible children from Year 1 who opted to participate. Overall, the incidence of unsolicited AEs was consistent with that of the open-label pediatric study of Dresden-manufactured H5N1 (A/Vietnam) vaccine in children aged 3-9 years [11].…”

“…Because children are vulnerable to influenza viruses and are important for viral transmission, they represent a target population for vaccination in the event of an influenza outbreak [9,10]. Therefore, to improve our understanding of pandemic influenza vaccines in this vulnerable group, the clinical trial program for AS03-adjuvanted avian-origin H5N1 influenza vaccines included large pediatric studies [11][12][13]. A Phase II-III randomized, placebo-controlled, observer-blind trial was conducted to assess the immunogenicity, reactogenicity, and safety of two 1.9 μg hemagglutinin (HA) doses of Québec-manufactured AS03 B -adjuvanted H5N1 (AS03 B -H5N1; A/Indonesia) vaccine in children aged from 6 months to <18 years recruited in Thailand, the United States (US), and Canada [14].…”

Adjuvanted influenza vaccines

“…In these studies, the adjuvanted vaccine solicited local and general symptoms more frequently, including pain, fatigue, headache and myalgia. Immunisation of children with an AS03 adjuvanted vaccine was also associated with transient injection site pain 86 . Similar results were seen with an AS03 adjuvanted H1N1 vaccine, the most frequently reported symptom was injection site pain 87 , and local and general symptoms were reported more frequently for AS03-adjuvanted H1N1 vaccine recipients than for controls 88,89 .…”

Influenza vaccines: Evaluation of the safety profile

“… 127 Adjuvanted and non-adjuvanted H5N1 vaccines are safe and well tolerated, though Diez-Domingo et al. 133 reported one potential immune-mediated disease (autoimmune hepatitis) related to vaccination.…”