Human polyclonal immunoglobulin G from transchromosomic bovines inhibits MERS-CoV in vivo
Human polyclonal immunoglobulin G from transchromosomic bovines inhibits MERS-CoV in vivo
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DOI：
10.1126/scitranslmed.aaf1061
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发表时间：
2016-02-17
影响因子：
17.1
通讯作者：
Frieman, Matthew B.
中科院分区：
文献类型：
--
作者：
Luke, Thomas;Wu, Hua;Frieman, Matthew B.
截至2015年11月13日，已向世界卫生组织报告了1618例中东呼吸综合征冠状病毒（中东呼吸综合征冠状病毒）实验室确诊人间感染病例，包括579例死亡。目前尚无经证实对中东呼吸综合征冠状病毒有价值的特异性预防或治疗药物。英国公共卫生部和国际严重急性呼吸道和新发感染联盟确定了中和抗体的被动免疫疗法作为一种值得优先研究的治疗方法。用两种实验性MERS-CoV疫苗接种两组经基因修饰的转染色体体（Tc）牛，使其产生大量的全人多克隆免疫球蛋白G （IgG）抗体。用γ辐照的a支全灭活病毒粒子疫苗（Jordan株）或B支刺突蛋白纳米颗粒疫苗（Al-Hasa株）接种，可获得具有高酶联免疫吸附测定（ELISA）和体外中和抗体滴度的Tc牛血清。两种纯化的Tc牛人IgG免疫球蛋白（Tc hIgG）， sabb -300（在Jordan菌株接种后产生）和sabb -301（在Al-Hasa菌株接种后产生）也具有较高的ELISA和中和抗体滴度，体外无抗体依赖性增强。sabb -301被选择用于体内和临床前研究。在Ad5-hDPP4受体转导小鼠感染MERS-CoV （Erasmus Medical Center 2012株）前12小时或感染后24小时和48小时单剂量给药，可迅速导致病毒肺滴度接近或低于检测极限。Tc牛，结合快速生产Tc hIgG和开发体外分析和动物模型的能力，可能提供一个平台，快速生产治疗方法，以预防和/或治疗MERS-CoV感染和/或其他新发传染病。
As of 13 November 2015, 1618 laboratory-confirmed human cases of Middle East respiratory syndrome coronavirus (MERS-CoV) infection, including 579 deaths, had been reported to the World Health Organization. No specific preventive or therapeutic agent of proven value against MERS-CoV is currently available. Public Health England and the International Severe Acute Respiratory and Emerging Infection Consortium identified passive immunotherapy with neutralizing antibodies as a treatment approach that warrants priority study. Two experimental MERS-CoV vaccines were used to vaccinate two groups of transchromosomic (Tc) bovines that were genetically modified to produce large quantities of fully human polyclonal immunoglobulin G (IgG) antibodies. Vaccination with a clade A gamma-irradiated whole killed virion vaccine (Jordan strain) or a clade B spike protein nanoparticle vaccine (Al-Hasa strain) resulted in Tc bovine sera with high enzyme-linked immunosorbent assay (ELISA) and neutralizing antibody titers in vitro. Two purified Tc bovine human IgG immunoglobulins (Tc hIgG), SAB-300 (produced after Jordan strain vaccination) and SAB-301 (produced after Al-Hasa strain vaccination), also had high ELISA and neutralizing antibody titers without antibody-dependent enhancement in vitro. SAB-301 was selected for in vivo and preclinical studies. Administration of single doses of SAB-301 12 hours before or 24 and 48 hours after MERS-CoV infection (Erasmus Medical Center 2012 strain) of Ad5-hDPP4 receptor-transduced mice rapidly resulted in viral lung titers near or below the limit of detection. Tc bovines, combined with the ability to quickly produce Tc hIgG and develop in vitro assays and animal model(s), potentially offer a platform to rapidly produce a therapeutic to prevent and/or treat MERS-CoV infection and/or other emerging infectious diseases.