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Clinical Trial
. 2015 Mar;9(2):68-77.
doi: 10.1111/irv.12295. Epub 2015 Feb 5.

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

Javier Díez-Domingo  1 , José-María Baldó, Maria Victoria Planelles-Catarino, María Garcés-Sánchez, Isabel Ubeda, Angels Jubert-Rosich, Josep Marès, Pilar Garcia-Corbeira, Philippe Moris, Maurice Teko, Carline Vanden Abeele, Paul Gillard
Affiliations
Clinical Trial

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

Javier Díez-Domingo et al. Influenza Other Respir Viruses. 2015 Mar.

Abstract

Background: An 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.

Methods: In 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).

Results: The 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 TH 1 profile were observed.

Conclusions: Two 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.

Keywords: AS03-adjuvanted; H5N1 influenza vaccine; cell-mediated immunity; children; pre-pandemic.

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Figures

Figure 1
Figure 1
Participant flow. TIV, inactivated trivalent influenza vaccine; AS03, tocopherol-based oil-in-water Adjuvant System; A, 11·86 mg tocopherol; B, 5·93 mg tocopherol; HA, hemagglutinin antigen; N, number of subjects in group (total vaccinated cohort); n, number of subjects with data available (per protocol cohort).
Figure 2
Figure 2
Immunogenicity in the per-protocol immunogenicity cohort (Day 42)† and the per-protocol persistence cohort (months 12 and 24). HA, hemagglutinin antigen; AS03, oil-in-water Adjuvant System containing 5·93 mg or 11·86 mg tocopherol (AS03B and AS03A, respectively); n, number of subjects with data available (per protocol cohort); CI, confidence limit; GMT, geometric mean titer; SCR, seroconversion rate (proportion of children with pre- and post-vaccination titers of >1:10 and ≥1:40, respectively, or pre-vaccination titers of ≥1:10 and ≥4-fold post-vaccination increase in titer); SPR, seroprotection rate (proportion of subjects with post-vaccination titer ≥1:40). †Day 42 results show the per-protocol immunogenicity cohort from the original study which has been previously published.
Figure 3
Figure 3
Cell-mediated immune responses against H5N1 vaccines in children from the per-protocol cohort for persistence. HA, hemagglutinin antigen; AS03, oil-in-water Adjuvant system containing 5·93 mg or 11·86 mg tocopherol (AS03B and AS03A, respectively); 1·9 μg HA/AS03B: n = 29 (D0, M12), n = 26 (D21), n = 27 (D42), n = 23 (M6), n = 25 (M24) 3·75 μg HA/AS03A: 3–5 years: n = 11 (D0, D42, M24), n = 10 (D21), and n = 15 (M6, M12); 6–9 years: n = 16 (D0, D42), n = 17 (D21), n = 14 (M6), n = 12 (M12), and n = 15 (M24). Values are expressed as medians with first and third quartiles for days (D) 0, 21, and 42 and months (M) 6, 12, and 24.
Figure 4
Figure 4
Cell-mediated immune responses against pool of peptides spanning the whole A/Vietnam/1194/2004 HA sequence in children from the per-protocol cohort for persistence. HA, hemagglutinin antigen; AS03, oil-in-water Adjuvant system containing 5·93 mg or 11·86 mg tocopherol (AS03B and AS03A, respectively); 1·9 μg HA/AS03B: n = 26 (D21), n = 24 (D42), n = 6 (M6), n = 24 (M24) 3·75 μg HA/AS03A: 3–5 years: n = 8 (D0), n = 9 (D21), n = 10 (M6, M12), n = 7 (M24); 6–9 years: n = 16 (D21), n = 14 (D42), n = 13 (M6), n = 10 (M12), and n = 14 (M24). Values are expressed as medians with first and third quartiles for days (D) 21, and 42 and months (M) 6, 12, and 24.
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