Protective neutralizing antibodies from human survivors of Crimean-Congo hemorrhagic fever.
Protective neutralizing antibodies from human survivors of Crimean-Congo hemorrhagic fever.
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DOI：
10.1016/j.cell.2021.05.001
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发表时间：
2021-06-24
期刊：
影响因子：
64.5
通讯作者：
Chandran K
中科院分区：
文献类型：
--
作者：
Fels JM;Maurer DP;Herbert AS;Wirchnianski AS;Vergnolle O;Cross RW;Abelson DM;Moyer CL;Mishra AK;Aguilan JT;Kuehne AI;Pauli NT;Bakken RR;Nyakatura EK;Hellert J;Quevedo G;Lobel L;Balinandi S;Lutwama JJ;Zeitlin L;Geisbert TW;Rey FA;Sidoli S;McLellan JS;Lai JR;Bornholdt ZA;Dye JM;Walker LM;Chandran K
克里米亚-刚果出血热病毒(CCHFV)是世界卫生组织的优先病原体。CCHFV感染导致一种高度致命的出血热，迫切需要特定的治疗和疫苗。在这里，我们描述了人类对自然CCHFV感染的免疫反应，以识别针对病毒糖蛋白的有效中和抗体(NAB)。竞争实验表明，这些NaB结合了GC亚基上的六个不同的抗原位点。通过突变进一步确定了这些位点，并将其映射到GC的融合模型上。成对筛选确定了提供协同中和作用的非竞争NAB的组合。通过双特异性抗体(BsAb)工程将协同NAB对的可变区物理连接，进一步增强了中和广度和效价。尽管在暴露前或暴露后的预防设置中，多个Nab保护小鼠免受致命的CCHFV攻击，但只有一种单抗DVD-121-801提供治疗保护。DVD-121-801是一种适合于临床开发的CCHFV治疗药物。通过从人类幸存者中分离出针对克里米亚-刚果出血热病毒糖蛋白的单抗，Fels等人。能够识别协同中和抗体的组合，并设计提供治疗保护的双特异性抗体
Crimean-Congo Hemorrhagic Fever Virus (CCHFV) is a World Health Organization priority pathogen. CCHFV infections cause a highly lethal hemorrhagic fever for which specific treatments and vaccines are urgently needed. Here, we characterize the human immune response to natural CCHFV infection to identify potent neutralizing antibodies (nAbs) targeting the viral glycoprotein. Competition experiments showed that these nAbs bind six distinct antigenic sites in the Gc subunit. These sites were further delineated through mutagenesis and mapped onto a prefusion model of Gc. Pairwise screening identified combinations of non-competing nAbs that afford synergistic neutralization. Further enhancements in neutralization breadth and potency were attained by physically linking variable domains of synergistic nAb pairs through bispecific antibody (bsAb) engineering. Although multiple nAbs protected mice from lethal CCHFV challenge in pre- or post-exposure prophylactic settings, only a single bsAb, DVD-121-801, afforded therapeutic protection. DVD-121-801 is a promising candidate suitable for clinical development as a CCHFV therapeutic. By isolating monoclonal antibodies against Crimean-Congo Hemorrhagic Fever Virus glycoproteins from human survivors, Fels et al. were able to identify combinations of synergistic neutralizing antibodies and engineer bispecific antibodies that provide therapeutic protection
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影响因子：
6.7
作者：
Austin SK;Dowd KA;Shrestha B;Nelson CA;Edeling MA;Johnson S;Pierson TC;Diamond MS;Fremont DH
通讯作者：
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影响因子：
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影响因子：
64.8
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通讯作者：
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影响因子：
6.4
作者：
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通讯作者：
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