Infectious Diseases Unit, Vaccine Evaluation Centre, University Hospitals of Leicester NHS Trust and Department of Infection, Immunity, and Inflammation, University of Leicester, UK.
Lancet Infect Dis. 2011 Feb;11(2):91-101. doi: 10.1016/S1473-3099(10)70296-6. Epub 2010 Dec 16.
BACKGROUND: Effective antigen-sparing vaccines are needed to confront pandemic influenza. Whole-virion and oil-in-water adjuvanted vaccines are the most effective formulations against H5N1 avian influenza. We assessed the safety and immunogenicity in adults in the UK of pandemic H1N1 whole-virion vaccine and oil-in-water adjuvanted vaccine purchased by the UK government in 2009. METHODS: In our randomised, observer-blind, parallel-group, controlled trial, healthy adults aged 18-44 years, 45-64 years, and 65 years and older (from Oct 19, to Nov 12, 2009) received two doses of vaccine given 21 days apart: either 7·5 μg of haemagglutinin formulated as whole-virion vaccine, or 3·75 μg of haemagglutinin formulated as split-virion vaccine with AS03(A) oil-in-water adjuvant. Assignment was by a computer-generated code, with random permuted blocks of two, four, and six. All participants and investigators were unaware of vaccine assignments. The trial was done at three hospitals in the UK. We measured antibody titres with a haemagglutination-inhibition assay at baseline; 7, 14, and 21 days after each vaccination; and at 6 months after the first dose. Primary outcome was vaccine immunogenicity of the full analysis set by the EU Committee of Human Medicinal Products licensing criteria. This study is registered with ISRCTN, number ISRCTN92328241. FINDINGS: At day 0, baseline antibody (titre ≥1/8) was detected in 44 (13%) of 347 participants. Sera from 95% to 98% of participants were assessed for immunogenicity on days 7, 14, 21, 28, 35, and 42, and at 6 months. On day 21 after one dose of adjuvanted AS03(A) or whole-virion vaccine, 63 (94%, 95 CI 85·4-98·4) of 67 and 50 (71%, 59·4-81·6) of 70 participants aged 18-44 years, 51 (77%, 65·3-86·7) of 66 and 26 (39%, 27·1-51·5) of 67 aged 45-64 years, and 19 (51%, 34·4-68·1) of 37 and 11 (32%, 17·4-50·5) of 34 aged 65 years or older had titres of 1:40 or greater. On day 42 (21 days after the second dose), 64 (100%, 94·4-100) of 64 and 49 (73%, 60·9-83·2) of 67 participants aged 18-44 years, 59 (91%, 81·0-96·5) of 65 and 29 (43·9%, 31·7-56·7) of 66 aged 45-64 years, and 28 (76%, 58·8-88·2) of 37 and 12 (36%, 20·4-54·9) of 33 aged 65 years or older had titres of 1/40 or greater. At 6 months, 62 (98%, 91·5-100) of 63 and 54 (78%, 66·7-87·3) of 69 participants aged 18-44 years, 54 (82%, 70·4-90·2) of 66 and 37 (55%, 42·6-67·4) of 67 aged 45-64 years, and 21 (57%, 39·5-72·9) of 37 and 10 (29%, 15·1-47·5) of 34 aged 65 years or older had titres of 1/40 or greater. There were no vaccine-related serious adverse events. Whole-virion vaccine was associated with fewer local and systemic reactions than adjuvanted vaccine. INTERPRETATION: AS03(A)-adjuvanted vaccine was more immunogenic against pandemic influenza A H1N1 virus than whole-virion vaccine and offers greater antigen-sparing capacity. A two-dose strategy should be considered for older people. FUNDING: Department of Health, National Institute for Health Research Evaluation, Trials and Studies Coordinating Centre.
背景：需要有效的抗原节约疫苗来应对大流行性流感。全病毒和油包水乳剂佐剂疫苗是针对 H5N1 禽流感最有效的制剂。我们评估了英国政府在 2009 年购买的大流行性 H1N1 全病毒疫苗和油包水乳剂佐剂疫苗在英国成年人中的安全性和免疫原性。
方法：在我们的随机、观察者盲、平行组、对照试验中，18-44 岁、45-64 岁和 65 岁及以上（2009 年 10 月 19 日至 11 月 12 日）的健康成年人接受了两种间隔 21 天的疫苗接种：7.5 μg 血凝素作为全病毒疫苗配制，或 3.75 μg 血凝素作为含 AS03(A)油包水乳剂佐剂的裂解病毒疫苗配制。通过计算机生成的代码，以随机排列的两、四和六个块进行分配。所有参与者和研究人员都不知道疫苗的分配情况。该试验在英国的三家医院进行。我们在基线时，在每次接种后 7、14 和 21 天，以及第一次接种后 6 个月，用血凝抑制试验测量抗体滴度。主要终点是欧盟人用药品许可委员会的全分析集疫苗免疫原性。这项研究在 ISRCTN 注册，编号 ISRCTN92328241。
结果：在第 0 天，347 名参与者中有 44 名（13%）基线时检测到抗体（滴度≥1/8）。95%至 98%的参与者的血清在第 7、14、21、28、35 和 42 天以及 6 个月时进行了免疫原性评估。一剂佐剂 AS03(A)或全病毒疫苗后第 21 天，18-44 岁年龄组的 67 名参与者中有 63 名（94%，95%CI 85.4-98.4），70 名参与者中有 50 名（71%，59.4-81.6），45-64 岁年龄组的 66 名参与者中有 66 名（77%，65.3-86.7），67 名参与者中有 26 名（39%，27.1-51.5），65 岁及以上年龄组的 37 名参与者中有 19 名（51%，34.4-68.1），11 名（32%，17.4-50.5）有 1:40 或更高的滴度。第 42 天（第二次接种后 21 天），18-44 岁年龄组的 64 名参与者中有 64 名（100%，94.4-100），67 名参与者中有 49 名（73%，60.9-83.2），45-64 岁年龄组的 65 名参与者中有 59 名（91%，81.0-96.5），66 名参与者中有 29 名（43.9%，31.7-56.7），65 岁及以上年龄组的 37 名参与者中有 28 名（76%，58.8-88.2），12 名（36%，20.4-54.9）有 1/40 或更高的滴度。6 个月时，18-44 岁年龄组的 63 名参与者中有 62 名（98%，91.5-100），69 名参与者中有 54 名（78%，66.7-87.3），45-64 岁年龄组的 66 名参与者中有 54 名（82%，70.4-90.2），67 名参与者中有 37 名（55%，42.6-67.4），65 岁及以上年龄组的 37 名参与者中有 21 名（57%，39.5-72.9），10 名（29%，15.1-47.5）有 1/40 或更高的滴度。没有与疫苗相关的严重不良事件。全病毒疫苗引起的局部和全身反应比含佐剂疫苗少。
解释：AS03(A)-佐剂疫苗对大流行性甲型 H1N1 流感病毒的免疫原性优于全病毒疫苗，具有更大的抗原节约能力。对于老年人，应考虑采用两剂策略。
资金：英国卫生部，国家卫生研究院评估、试验和研究协调中心。
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