一种用改良痘苗病毒安卡拉加强免疫的单价黑猩猩腺病毒埃博拉疫苗。
A Monovalent Chimpanzee Adenovirus Ebola Vaccine Boosted with MVA.
作者信息
Ewer Katie, Rampling Tommy, Venkatraman Navin, Bowyer Georgina, Wright Danny, Lambe Teresa, Imoukhuede Egeruan B, Payne Ruth, Fehling Sarah Katharina, Strecker Thomas, Biedenkopf Nadine, Krähling Verena, Tully Claire M, Edwards Nick J, Bentley Emma M, Samuel Dhanraj, Labbé Geneviève, Jin Jing, Gibani Malick, Minhinnick Alice, Wilkie Morven, Poulton Ian, Lella Natalie, Roberts Rachel, Hartnell Felicity, Bliss Carly, Sierra-Davidson Kailan, Powlson Jonathan, Berrie Eleanor, Tedder Richard, Roman Francois, De Ryck Iris, Nicosia Alfredo, Sullivan Nancy J, Stanley Daphne A, Mbaya Olivier T, Ledgerwood Julie E, Schwartz Richard M, Siani Loredana, Colloca Stefano, Folgori Antonella, Di Marco Stefania, Cortese Riccardo, Wright Edward, Becker Stephan, Graham Barney S, Koup Richard A, Levine Myron M, Volkmann Ariane, Chaplin Paul, Pollard Andrew J, Draper Simon J, Ballou W Ripley, Lawrie Alison, Gilbert Sarah C, Hill Adrian V S
机构信息
From the Jenner Institute and Centre for Clinical Vaccinology and Tropical Medicine, University of Oxford, and the National Institute for Health Research Oxford Biomedical Research Centre, Oxford (K.E., T.R., N.V., G.B., D.W., T.L., E.B.I., R.P., C.M.T., N.J.E., G.L., J.J., M.G., A.M., M.W., I.P., N.L., R.R., F.H., C.B., K.S.-D., J.P., E.B., A.J.P., S.J.D., A.L., S.C.G., A.V.S.H.), and Viral Pseudotype Unit, Faculty of Science and Technology, University of Westminster (E.M.B., E.W.), and Virus Reference Department, Public Health Agency (D.S., R.T.), London - all in the United Kingdom; the Institute of Virology, Philipps University Marburg (S.K.F., T.S., N.B., V.K., S.B.), and German Center for Infection Research, Partner Site Giessen-Marburg-Langen (S.B.), Marburg, and Bavarian Nordic, Martinsried (A.V., P.C.) - all in Germany; GlaxoSmithKline Biologicals, Rixensart, Belgium (F.R., I.D.R., W.R.B.); ReiThera, Rome (A.N., L.S., S.C., A.F., S.D.M.), and CEINGE and the Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples (A.N.) - both in Italy; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda (N.J.S., D.A.S., O.T.M., J.E.L., R.M.S., B.S.G., R.A.K.), and the Center for Vaccine Development, University of Maryland School of Medicine, Baltimore (M.M.L.) - both in Maryland; and Keires, Basel, Switzerland (R.C.).
出版信息
N Engl J Med. 2016 Apr 28;374(17):1635-46. doi: 10.1056/NEJMoa1411627. Epub 2015 Jan 28.
BACKGROUND
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.
METHODS
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--1×10(10) viral particles, 2.5×10(10) viral particles, and 5×10(10) 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.
RESULTS
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).
CONCLUSIONS
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.).
背景
2014年达到高峰的西非埃博拉病毒病疫情已导致超过11000人死亡。研发有效的埃博拉疫苗是控制未来疫情爆发的当务之急。
方法
在这项1期研究中，我们给英国牛津的60名健康成年志愿者单次接种了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（ChAd3）疫苗。疫苗以三种剂量水平给药——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，我们在60名参与者中的30名中评估了添加一剂编码相同埃博拉病毒糖蛋白的改良安卡拉痘苗病毒（MVA）株加强免疫的效果，并在另外16名参与者中评估了缩短初免-加强免疫间隔的效果。我们还将针对灭活全埃博拉病毒颗粒的抗体反应和中和抗体活性与在一项表达ZEBOV糖蛋白的重组水疱性口炎病毒疫苗（rVSV-ZEBOV）的1期研究中观察到的结果进行比较，以确定相对效力并评估持久性。
结果
在所研究的任何剂量水平下均未发现安全问题。用ChAd3疫苗免疫四周后，ZEBOV特异性抗体反应与rVSV-ZEBOV疫苗诱导的反应相似，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载体加强免疫使病毒特异性抗体增加了12倍（几何平均滴度为9007），并使糖蛋白特异性CD8⁺T细胞增加了5倍。在所有30名参与者加强免疫后，中和抗体均显著增加（几何平均滴度为139；P<0.001）。接种ChAd3疫苗的参与者在接种后6个月病毒特异性抗体反应仍为阳性（几何平均滴度为758），但接受MVA加强免疫的参与者中抗体反应显著更高（几何平均滴度为1750；P<0.001）。
结论
用MVA加强免疫的ChAd3疫苗引发了针对ZEBOV的B细胞和T细胞免疫反应，优于单独使用ChAd3疫苗诱导的反应。（由惠康信托基金会及其他机构资助；ClinicalTrials.gov编号，NCT02240875。）
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