Vaccines, Immunoprophylaxis, and Immunotherapy for Coronaviruses

已经评估了几种用于MERS-CoV研究的动物模型。简而言之，非人灵长类动物已被用作MERS的感染模型，其中恒河猴表现出轻度感染，而绒猴表现出更严重的疾病。虽然小鼠对MERS-CoV的实验感染天然不敏感，但已经产生了表达人二肽基肽酶4（DPP 4）受体的几种小鼠模型。 新西兰白色兔天然地展示允许MERS-CoV附着和感染的DPP 4分子，并且它们可以实验性地感染MERS-CoV，导致具有轻度肺部炎症的无症状感染。病毒滴度在接种后约三天达到峰值。 由于MERS-CoV在兔模型中的感染可以通过病理学和病毒复制来监测，因此我们评估了该模型以测试潜在的医学对策。 中东呼吸综合征冠状病毒（MERS-CoV）作为严重呼吸道疾病的一个原因的出现突出了制定医疗对策的必要性。美国国家癌症研究所的科学家从健康人的大型噬菌体展示文库中分离出一种人单克隆抗体（hmAb）m336，该抗体与MERS-CoV刺突蛋白的受体结合结构域相互作用，并在体外对MERS-CoV显示出异常有效的中和活性。 我们与NCI的同事合作，评估了这种hmAb在兔模型中预防MERS-CoV感染的有效性。经静脉和鼻内途径给予m336预防后，肺中的病毒RNA滴度显著降低。在感染的一天内，我们观察到肺部病毒RNA载量减少40至9000倍，炎症和病毒抗原存在最小。这些结果表明，暴露前给予的m336抗体能够预防MERS-CoV感染，并保证进一步开发作为针对MERS-CoV感染的医学对策。

Several animal models have been evaluated for the study of MERS-CoV. In brief, non-human primates have been utilized as infection models of MERS, with rhesus macaques displaying mild infection and marmosets more severe disease. While mice are not naturally susceptible to experimental infection with MERS-CoV, several mouse models have been generated expressing the human dipeptidyl peptidase 4 (DPP4) receptor. New Zealand white rabbits naturally display a DPP4 molecule that allows for attachment and infection by MERS-CoV and they can be experimentally infected with MERS-CoV, resulting in asymptomatic infection with mild pulmonary inflammation. Viral titers peak about three days post-inoculation. Because MERS-CoV infection in the rabbit model can be monitored by pathology and viral replication, we evaluated this model for testing a potential medical countermeasure. The emergence of Middle East respiratory syndrome coronavirus (MERS-CoV) as a cause of severe respiratory disease highlights the need for development of medical countermeasures. Scientists at the National Cancer Institute isolated a human monoclonal antibody (hmAb) m336, from a large phage-display library from healthy humans that interacts with the receptor-binding domain of the MERS-CoV spike protein and shows exceptionally potent neutralizing activity against MERS-CoV in vitro. In collaboration with colleagues at NCI, we evaluated the efficacy of this hmAb administered as prophylaxis for MERS-CoV infection in the rabbit model. Significant reduction in viral RNA titers was demonstrated in the lungs following prophylaxis with m336 by the intravenous and intranasal routes. Within one day of infection we observed between a 40 to 9000-fold reduction in pulmonary viral RNA load, with minimal inflammation and viral antigen present. These results indicate the m336 antibody administered prior to exposure is able to prevent MERS-CoV infection and warrants further development as a medical countermeasure against MERS-CoV infection.