Madan Anuradha, Ferguson Murdo, Sheldon Eric, Segall Nathan, Chu Laurence, Toma Azhar, Rheault Paul, Friel Damien, Soni Jyoti, Li Ping, Innis Bruce L, Schuind Anne
GSK, 1250 South Collegeville Road, Collegeville, PA 19426, USA.
Colchester Research Group, 68 Robie Street, Truro, Nova Scotia B2N 1L2, Canada.
Vaccine. 2017 Mar 7;35(10):1431-1439. doi: 10.1016/j.vaccine.2017.01.054. Epub 2017 Feb 7.
H7 influenza strains have pandemic potential. AS03-adjuvanted H7N1 A/mallard/Netherlands/12/2000 split-virion vaccine formulations were evaluated as model H7-subtype vaccine and tested after H7N9 emerged in China, and caused severe human disease with high mortality.
In this phase I/II, observer-blind, randomized trial in US and Canada, 420 healthy adults (21-64years) were randomized to receive 1 of 4 H7N1 vaccine formulations (3.75 or 7.5μg hemagglutinin adjuvanted with either AS03 or AS03), 15μg unadjuvanted H7N1 hemagglutinin, or saline placebo, given as 2-dose series. Immunogenicity was assessed using hemagglutination-inhibition (HI) and microneutralization (MN) assays, at day 42 (21days post-dose 2), month 6, and month 12 (HI only) for the per-protocol cohorts (398, 379 and 368 participants, respectively). Safety is reported up to month 12.
Beneficial AS03 adjuvant effect was demonstrated. Committee for Medical Products for Human Use, and Center for Biologics Evaluation and Research (CBER) criteria were met for all adjuvanted formulations at day 42 (H7N1 HI assay); seroprotection (SPR) and seroconversion rates (SCR) were 88.5-94.8%, mean geometric increase (MGI) 19.2-34.9, and geometric mean titers (GMT) 98.3-180.7. Unadjuvanted H7N1 vaccine did not meet CBER criteria. In adjuvanted groups, antibody titers decreased over time; month 12 SPRs and GMTs were low (2.0-18.8% and 8.1-12.2). MN antibodies showed similar kinetics, with titers persisting at higher range than HI at month 6. All adjuvanted groups showed cross-reactivity against H7N9, with HI responses similar to H7N1. The most frequent solicited symptom in adjuvanted groups was injection site pain (71.2-86.7%); grade 3 solicited symptoms were infrequent. Nine participants reported 17 serious adverse events; none were considered causally related to vaccination.
Adjuvanted H7N1 vaccine formulations had an acceptable safety profile and induced an antibody response after 2 doses with cross-reactivity to H7N9. ClinicalTrials.gov: NCT01934127.
H7流感毒株具有大流行潜力。AS03佐剂的H7N1 A/绿头鸭/荷兰/12/2000裂解病毒疫苗制剂作为H7亚型疫苗模型进行了评估，并在中国出现H7N9且导致严重人类疾病和高死亡率后进行了测试。
在这项在美国和加拿大进行的I/II期、观察者盲法、随机试验中，420名健康成年人（21 - 64岁）被随机分配接受4种H7N1疫苗制剂中的1种（3.75或7.5μg血凝素，佐以AS03或AS03B）、15μg无佐剂的H7N1血凝素或生理盐水安慰剂，按2剂程序接种。在第42天（第2剂接种后21天）、第6个月和第12个月（仅HI检测）对符合方案队列（分别为398、379和368名参与者）使用血凝抑制（HI）和微量中和（MN）试验评估免疫原性。报告了至第12个月的安全性。
证实了AS03佐剂的有益效果。在第42天（H7N1 HI检测），所有佐剂制剂均符合人用药品委员会以及生物制品评估和研究中心（CBER）的标准；血清保护率（SPR）和血清转化率（SCR）为88.5 - 94.8%，平均几何增加倍数（MGI）为19.2 - 34.9，几何平均滴度（GMT）为98.3 - 180.7。无佐剂的H7N1疫苗未达到CBER标准。在佐剂组中，抗体滴度随时间下降；第12个月的SPR和GMT较低（2.0 - 18.8%和8.1 - 12.2）。MN抗体表现出相似的动力学，在第6个月时滴度维持在比HI更高的范围。所有佐剂组均显示出对H7N9的交叉反应性，HI反应与H7N1相似。佐剂组中最常见的自发症状是注射部位疼痛（71.2 - 86.7%）；3级自发症状很少见。9名参与者报告了17起严重不良事件；均未被认为与疫苗接种有因果关系。
佐剂H7N1疫苗制剂具有可接受的安全性，接种2剂后可诱导抗体反应，并对H7N9具有交叉反应性。ClinicalTrials.gov：NCT01934127。
