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以黑猩猩腺病毒为载体的埃博拉疫苗
Chimpanzee Adenovirus Vector Ebola Vaccine


Julie E. Ledgerwood ... 其他 • 2017.03.09

埃博拉疫苗带给中国疫苗研发的启示

 

戴连攀†*,严景华‡,施一§,高福†§¶

† 中国科学院北京生命科学研究院免疫与健康联合研究中心;‡ 中国科学院微生物研究所微生物生理与代谢工程重点实验室;§ 中国科学院微生物研究所病原微生物与免疫学重点实验室;¶ 中国疾病预防控制中心病毒病预防控制所

*通讯作者

 

2014年起西非暴发了前所未有的埃博拉疫情,上万人因为感染埃博拉病毒而死亡。世界卫生组织宣布埃博拉疫情成为国际公共卫生紧急事件,之后疫苗的研发大大提速。已确定埃博拉病毒分5个亚型,即扎伊尔型、苏丹型、本迪布焦型、塔伊森林型和莱斯顿型。苏丹型和扎伊尔型对人类和非人灵长类动物的致死率很高。本期的《新英格兰医学杂志》发表了一篇黑猩猩3型腺病毒载体埃博拉疫苗的1期临床试验研究报告1。该疫苗将表达两种不同型(扎伊尔型和苏丹型)糖蛋白的黑猩猩腺病毒疫苗混合制成二价苗,接种20名受试者显示出良好的安全性与免疫原性。免疫反应发生率及反应强度都与疫苗接种剂量正相关,其中高剂量组疫苗(2×1011单位颗粒)能够刺激机体产生持续(大于48周)的保护性免疫反应。该疫苗正在进一步展开2期临床试验。

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摘要


背景

2014年埃博拉病毒病(EVD)史无前例的流行引发了国际性的反应,加快了预防性疫苗的问世。一种以复制上有缺陷的重组黑猩猩3型腺病毒为载体的埃博拉疫苗(cAd3-EBO),编码来自扎伊尔型和苏丹型(埃博拉病毒)的糖蛋白,为非人灵长类动物模型提供了防护。该疫苗迅速进入了1期临床评估。

 

方法

我们进行了一项剂量递增、开放标签的1期cAd3-EBO试验。将20名健康成人按招募顺序分为两组,每组10人,均通过肌内注射的方式接种疫苗,剂量为2×1010或2×1011颗粒单位。在接种疫苗后的前8周期间对涉及安全性和免疫原性的主要和次要终点进行了评估;此外,在接种疫苗后的48周对疫苗的长期持久性进行了评估。

 

结果

在这项小型研究中,未发现安全方面的问题;然而,2名接受了2×1011颗粒单位剂量的参与者在接种疫苗后一日内出现短暂的发热。全部20名参与者体内均诱导产生糖蛋白特异性抗体;接受2×1011颗粒单位的组中,抗体滴度比接受2×1010颗粒单位的组高(第4周时抗扎伊尔型抗原几何平均滴度,2,037对331;P=0.001)。接受2×1011颗粒单位的组中,糖蛋白特异性T细胞应答比接受2×1010颗粒单位的组更常出现。第4周时两组产生CD4应答的人数分别为全部10名参与者和10名参与者中的3名(P=0.004),产生CD8应答的人数为10名参与者中的7名和10名参与者中的2名(P=0.07)。抗体反应持久性的评估表明,在48周时仍然保持了较高的抗体滴度,最高的抗体滴度都见于接受2×1011颗粒单位组的参与者中。

 

结论

cAd3-EBO疫苗的反应原性及其诱导的免疫应答具有剂量依赖性。使用非人灵长类的疫苗攻毒研究表明,2×1011颗粒单位剂量产生的扎伊尔型糖蛋白特异性抗体应答在与疫苗诱导的保护性免疫相关的范围内,且应答可持续至第48周。评估cAd3-EBO的2期试验和有效性试验正在进行(本研究由美国国立卫生研究院[National Institutes of Health,NIH]院内研究项目[Intramural Research Program]资助;VRC 207在ClinicalTrials.gov注册号为NCT02231866)。





作者信息

Julie E. Ledgerwood, D.O., Adam D. DeZure, M.D., Daphne A. Stanley, M.S., Emily E. Coates, Ph.D., Laura Novik, M.A., Mary E. Enama, M.A., Nina M. Berkowitz, M.P.H., Zonghui Hu, Ph.D., Gyan Joshi, M.S., Aurélie Ploquin, Ph.D., Sandra Sitar, M.S., Ingelise J. Gordon, R.N., Sarah A. Plummer, C.R.N.P., LaSonji A. Holman, F.N.P., Cynthia S. Hendel, C.R.N.P., Galina Yamshchikov, M.S., Francois Roman, M.D., Alfredo Nicosia, Ph.D., Stefano Colloca, Ph.D., Riccardo Cortese, M.D., Robert T. Bailer, Ph.D., Richard M. Schwartz, Ph.D., Mario Roederer, Ph.D., John R. Mascola, M.D., Richard A. Koup, M.D., Nancy J. Sullivan, Ph.D., and Barney S. Graham, M.D., for the VRC 207 Study Team*
From the Vaccine Research Center (J.E.L., A.D.D., D.A.S., E.E.C., L.N., M.E.E., N.M.B., A.P., S.S., I.J.G., S.A.P., L.A.H., C.S.H., G.Y., R.T.B., R.M.S., M.R., J.R.M., R.A.K., N.J.S., B.S.G.) and the Biostatistics Research Branch, Division of Clinical Research (Z.H., G.J.), National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD; GlaxoSmithKline Vaccines, Rixensart, Belgium (F.R.); ReiThera, Rome (A.N., S.C.), and CEINGE and the Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples (A.N.) — both in Italy; and Keires, Basel, Switzerland (R.C.). Address reprint requests to Dr. Ledgerwood at ledgerwood@mail.nih.gov. *A complete list of members of the VRC 207 Study Team is provided in the Supplementary Appendix, available at NEJM.org.

 

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