Serological Responses to an Avian Influenza A/H7N9 Vaccine Mixed at the Point-of-Use With MF59 Adjuvant A Randomized Clinical Trial
Serological Responses to an Avian Influenza A/H7N9 Vaccine Mixed at the Point-of-Use With MF59 Adjuvant A Randomized Clinical Trial
复制标题
DOI：
10.1001/jama.2014.12854
复制
发表时间：
2014-10-08
影响因子：
120.7
通讯作者：
Bellamy, Abbie R.
中科院分区：
文献类型：
--
作者：
Mulligan, Mark J.;Bernstein, David I.;Bellamy, Abbie R.
重要性人感染禽流感A/H7N9在中国已导致高发病率和死亡率。目的比较不同剂量的A/Shanghai/2/13（H7N9）流感疫苗与MF59佐剂混合或不混合的安全性和免疫原性。从2013年9月开始，在4个美国研究中心进行的II期试验招募了700名年龄在19至64岁之间的成年人;干预H7N9灭活病毒疫苗在第0天和第21天以标称剂量3.75，7.5、15或45 μ g血凝素（实际剂量高约50%），有或没有MF 59佐剂。共有99、100或101名参与者被随机分配到每组（7组; N = 700）.主要结果和测量达到第42天抗体滴度为40或更高或血清转化的比例（通过血凝抑制试验，滴度至少增加4倍，达到>= 40）;截至第13个月，出现疫苗相关严重不良事件;结果受试者接种无佐剂疫苗后血凝抑制抗体最低。在接受2剂3.75 μ g剂量的H7N9疫苗加MF59佐剂后，58名参与者在第42天发生血清转化（59%; 95%CI，48%-68%）。在62名参与者中，峰值血清转换发生在第29天（62%; 95% CI，52%-72%）。第42天的几何平均滴度为33.0（95% CI，24.7 - 44.1）。较高的抗原剂量与应答增加无关。对于中和抗体测定，在接受3.75 μ g H7N9疫苗加MF59佐剂后，81名参与者在第42天发生血清转化（82%; 95%CI，73%-89%）。第42天的几何平均滴度为81.4（95% CI，66.6 - 99.5）。在第42天将佐剂与第一次或两次15 μ g剂量混合后，在血凝抑制血清转化方面没有统计学显著差异（分别为n = 34 [35%; 95%CI，25%-45%] vs n = 47 [47%; 95%CI，37%-58%]; P = 0.10）。近期接受季节性流感疫苗接种和年龄较大与应答减弱相关。未发生与疫苗相关的严重不良事件。征集疫苗接种后的症状一般是轻微的，更多的局部症状，看到在参与者谁收到的adjuvant.CONCLUSIONS和RELEVANCE点的使用混合和管理的2个剂量的H7N9疫苗在最低测试抗原剂量与MF59佐剂产生血清转化的参与者在59%。虽然这些发现表明这种方法的潜在价值，但该研究受到缺乏超过42天的抗体数据和缺乏临床结果的限制。
IMPORTANCE Human infections with avian influenza A/H7N9 have resulted in high morbidity and mortality in China.OBJECTIVE To compare safety and immunogenicity of different doses of influenza A/Shanghai/2/13 (H7N9) vaccine mixed with or without the MF59 adjuvant.DESIGN, SETTING, AND PARTICIPANTS Multicenter, randomized, double-blind, phase 2 trial at 4 US sites enrolled 700 adults aged 19 to 64 years beginning in September 2013; 6-month follow-up was completed in May 2014.INTERVENTIONS The H7N9 inactivated virus vaccine was administered intramuscularly on days 0 and 21 at nominal doses of 3.75, 7.5, 15, or 45 mu g of hemagglutinin (actual doses approximately 50% higher) with or without the MF59 adjuvant. A total 99, 100, or 101 participants were randomized to each group (7 groups; N = 700).MAIN OUTCOMES AND MEASURES Proportions achieving day 42 antibody titer of 40 or greater or seroconversion (a minimum 4-fold increase to titer >= 40) with the hemagglutination inhibition assay; vaccine-related serious adverse events through month 13; and solicited postvaccination symptoms through day 7.RESULTS Hemagglutination inhibition antibodies were minimal after participants received an unadjuvanted vaccine. After receiving 2 doses of H7N9 vaccine at a dosage of 3.75 mu g plus the MF59 adjuvant, day 42 seroconversion occurred in 58 participants (59%; 95% CI, 48%-68%). The peak seroconversion occurred at day 29 in 62 participants (62%; 95% CI, 52%-72%). The day 42 geometric mean titer was 33.0 (95% CI, 24.7-44.1). Higher antigen doses were not associated with increased response. For the neutralizing antibody assays, after receiving 3.75 mu g of H7N9 vaccine plus the MF59 adjuvant, day 42 seroconversion occurred in 81 participants (82%; 95% CI, 73%-89%). The day 42 geometric mean titer was 81.4 (95% CI, 66.6-99.5). There was no statistically significant difference in day 42 hemagglutination inhibition seroconversion after mixing adjuvant with either the first or both 15 mu g doses (n = 34 [35%; 95% CI, 25%-45%] vs n = 47 [47%; 95% CI, 37%-58%], respectively; P = .10). Recent receipt of seasonal influenza vaccination and older age were associated with attenuated response. No vaccine-related serious adverse events occurred. Solicited postvaccination symptoms were generally mild with more local symptoms seen in participants who received the adjuvant.CONCLUSIONS AND RELEVANCE Point-of-use mixing and administration of 2 doses of H7N9 vaccine at the lowest tested antigen dose with MF59 adjuvant produced seroconversion in 59% of participants. Although these findings indicate potential value in this approach, the study is limited by the absence of antibody data beyond 42 days and the absence of clinical outcomes.