A Monovalent Chimpanzee Adenovirus Ebola Vaccine Boosted with MVA.
A Monovalent Chimpanzee Adenovirus Ebola Vaccine Boosted with MVA.
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DOI：
10.1056/nejmoa1411627
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发表时间：
2016-04-28
期刊：
影响因子：
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通讯作者：
Hill AV
中科院分区：
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作者：
Ewer K;Rampling T;Venkatraman N;Bowyer G;Wright D;Lambe T;Imoukhuede EB;Payne R;Fehling SK;Strecker T;Biedenkopf N;Krähling V;Tully CM;Edwards NJ;Bentley EM;Samuel D;Labbé G;Jin J;Gibani M;Minhinnick A;Wilkie M;Poulton I;Lella N;Roberts R;Hartnell F;Bliss C;Sierra-Davidson K;Powlson J;Berrie E;Tedder R;Roman F;De Ryck I;Nicosia A;Sullivan NJ;Stanley DA;Mbaya OT;Ledgerwood JE;Schwartz RM;Siani L;Colloca S;Folgori A;Di Marco S;Cortese R;Wright E;Becker S;Graham BS;Koup RA;Levine MM;Volkmann A;Chaplin P;Pollard AJ;Draper SJ;Ballou WR;Lawrie A;Gilbert SC;Hill AV
2014年达到高峰的西非埃博拉病毒病疫情已造成11,000多人死亡。开发有效的埃博拉疫苗是控制未来疫情的优先事项。在这项1期研究中，我们在英国牛津向60名健康成年志愿者接种了单剂量的编码扎伊尔埃博拉病毒（ZEBOV）表面糖蛋白的黑猩猩腺病毒3型（ChAd 3）疫苗。该疫苗以三种剂量水平接种- 1×1010病毒颗粒，2.5×1010病毒颗粒和5×1010病毒颗粒-每组20名参与者。然后，我们评估了在60名参与者中的30名中添加编码相同埃博拉病毒糖蛋白的改良安卡拉牛痘（MVA）菌株的加强剂量的效果，并评估了另外16名参与者中减少的初免-加强间隔。我们还将对灭活的完整埃博拉病毒病毒粒子的抗体应答和中和抗体活性与表达ZEBOV糖蛋白的重组水泡性口炎病毒疫苗（rVSV-ZEBOV）的1期研究中观察到的抗体应答和中和抗体活性进行了比较，以确定相对效力并评估耐久性。在研究的任何剂量水平下均未发现安全性问题。用ChAd 3疫苗免疫后四周，ZEBOV特异性抗体应答与rVSV-ZEBOV疫苗接种诱导的那些相似，几何平均滴度分别为752和921。两种疫苗的ZEBOV中和活性也相似（几何平均滴度，分别为14.9和22.2）。用MVA载体加强免疫可使病毒特异性抗体增加12倍（几何平均滴度，9007），并使糖蛋白特异性CD 8 + T细胞增加5倍。在所有30名参与者中，在加强免疫后观察到中和抗体的显著增加（几何平均滴度，139; P<0.001）。在接种ChAd 3的参与者中，病毒特异性抗体应答在接种后6个月仍为阳性（几何平均滴度，758），但在接受MVA加强剂的参与者中显著更高（几何平均滴度，1750; P<0.001）。用MVA加强的ChAd 3疫苗引发对ZEBOV的B细胞和T细胞免疫应答，其上级于单独的ChAd 3疫苗诱导的那些。（由Wellcome Trust和其他人资助; ClinicalTrials.gov编号，NCT 02240875。
The West African outbreak of Ebola virus disease that peaked in 2014 has caused more than 11,000 deaths. The development of an effective Ebola vaccine is a priority for control of a future outbreak. In this phase 1 study, we administered a single dose of the chimpanzee adenovirus 3 (ChAd3) vaccine encoding the surface glycoprotein of Zaire ebolavirus (ZEBOV) to 60 healthy adult volunteers in Oxford, United Kingdom. The vaccine was administered in three dose levels — 1×1010 viral particles, 2.5×1010 viral particles, and 5×1010 viral particles — with 20 participants in each group. We then assessed the effect of adding a booster dose of a modified vaccinia Ankara (MVA) strain, encoding the same Ebola virus glycoprotein, in 30 of the 60 participants and evaluated a reduced prime–boost interval in another 16 participants. We also compared antibody responses to inactivated whole Ebola virus virions and neutralizing antibody activity with those observed in phase 1 studies of a recombinant vesicular stomatitis virus–based vaccine expressing a ZEBOV glycoprotein (rVSV-ZEBOV) to determine relative potency and assess durability. No safety concerns were identified at any of the dose levels studied. Four weeks after immunization with the ChAd3 vaccine, ZEBOV-specific antibody responses were similar to those induced by rVSV-ZEBOV vaccination, with a geometric mean titer of 752 and 921, respectively. ZEBOV neutralization activity was also similar with the two vaccines (geometric mean titer, 14.9 and 22.2, respectively). Boosting with the MVA vector increased virus-specific antibodies by a factor of 12 (geometric mean titer, 9007) and increased glycoprotein-specific CD8+ T cells by a factor of 5. Significant increases in neutralizing antibodies were seen after boosting in all 30 participants (geometric mean titer, 139; P<0.001). Virus-specific antibody responses in participants primed with ChAd3 remained positive 6 months after vaccination (geometric mean titer, 758) but were significantly higher in those who had received the MVA booster (geometric mean titer, 1750; P<0.001). The ChAd3 vaccine boosted with MVA elicited B-cell and T-cell immune responses to ZEBOV that were superior to those induced by the ChAd3 vaccine alone. (Funded by the Wellcome Trust and others; ClinicalTrials.gov number, NCT02240875.)