AVIR Green Hills Biotechnology, 1200 Vienna, Austria.
AVIR Green Hills Biotechnology, 1200 Vienna, Austria.
Vaccine. 2019 Jun 19;37(28):3722-3729. doi: 10.1016/j.vaccine.2019.05.013. Epub 2019 May 30.
Traditional inactivated influenza vaccines are the type of vaccines that were most frequently developed for immunization against the highly pathogenic avian H5N1 influenza virus. However, clinical trials with inactivated influenza vaccines for H5N1 indicated that high doses and at least two immunizations are required for an effective immune response (Nicholson et al., 2001; Treanor, Campbell et al., 2006; Treanor, Schiff et al., 2006; Ehrlich et al., 2008). We investigated the safety and immunogenicity of a live attenuated H5N1 vaccine (delNS1-H5N1) lacking the interferon antagonist nonstructural protein 1 (NS1).
We conducted a double-blind, placebo-controlled, phase 1 study in healthy adult participants who were randomly assigned at a 2:1 ratio to receive two immunizations of delNS1-H5N1 vaccine at 6.8 log10 50% tissue culture infectious doses (TCID)/subject or 7.5 log10 TCID/subject, or placebo.
Intranasal vaccination with the live attenuated delNS1-H5N1 vaccine was safe and well tolerated. The most common adverse events identified were symptoms associated with mild influenza infections, such as increased body temperature (>37.0 °C), pharyngeal erythema, rhinitis and throat irritation, and were reported within 7 days after the first immunization. delNS1-H5N1 was able to induce significant vaccine-specific serum antibody titers even at the lower dose level of 6.8 log10 TCID/subject. Seroconversion occurred in 75% of study participants after only one immunization with 7.5 log10 TCID/subject. Vaccine-specific local IgA responses were observed in 41.7% of individuals that showed serum antibody responses after 2nd immunization.
We show that vaccination with a live attenuated H5N1 influenza vaccine lacking NS1 is safe and induces significant levels of vaccine-specific antibodies even after one immunization. The safety and immunogenicity data indicate that delNS1-H5N1 has the potential to fulfil the unmet need for an effective influenza vaccine in pandemic situations. (ClinicalTrials.gov identifier NCT03745274).
传统的灭活流感疫苗是最常用于针对高致病性禽流感 H5N1 流感病毒免疫接种的疫苗类型。然而，针对 H5N1 的灭活流感疫苗的临床试验表明，高剂量和至少两次免疫接种对于有效免疫反应是必需的（Nicholson 等人，2001 年；Treanor、Campbell 等人，2006 年；Treanor、Schiff 等人，2006 年；Ehrlich 等人，2008 年）。我们研究了缺乏干扰素拮抗剂非结构蛋白 1（NS1）的活减毒 H5N1 疫苗（delNS1-H5N1）的安全性和免疫原性。
我们在健康成年参与者中进行了一项双盲、安慰剂对照、1 期研究，参与者以 2:1 的比例随机分配接受两次免疫接种，剂量分别为 6.8 log1050%组织培养感染剂量（TCID）/受试者或 7.5 log10 TCID/受试者的 delNS1-H5N1 疫苗或安慰剂。
鼻内接种活减毒 delNS1-H5N1 疫苗是安全且耐受良好的。最常见的不良事件是与轻度流感感染相关的症状，如体温升高（>37.0°C）、咽红斑、鼻炎和喉咙刺激，这些症状在第一次免疫接种后 7 天内报告。即使在较低的 6.8 log10 TCID/受试者剂量水平下，delNS1-H5N1 也能够诱导显著的疫苗特异性血清抗体滴度。7.5 log10 TCID/受试者剂量的单次免疫即可使 75%的研究参与者发生血清抗体转换。在第二次免疫接种后出现血清抗体反应的 41.7%个体中观察到疫苗特异性局部 IgA 反应。
我们表明，接种缺乏 NS1 的活减毒 H5N1 流感疫苗是安全的，即使在一次免疫接种后也能诱导显著水平的疫苗特异性抗体。安全性和免疫原性数据表明，delNS1-H5N1 有可能满足大流行情况下对有效流感疫苗的未满足需求。（ClinicalTrials.gov 标识符 NCT03745274）。
