Pre-clinical evaluation of an adenoviral-based MERS-CoV vaccine

 描述(申请人提供)：中东呼吸综合征冠状病毒(MERS-CoV)最近成为人类严重呼吸道疾病的病原体。迄今已确诊206例中东呼吸综合征冠状病毒感染病例，包括71例死亡。大多数感染病例在地理上与中东有关，但英国、德国、法国、意大利和西班牙也出现了病例。单峰骆驼很可能是MERS冠状病毒的宿主。MERS冠状病毒尖峰蛋白(S)是病毒包膜的特征结构成分，被认为是抗冠状病毒感染疫苗的关键靶点，正如我们和其他人先前已经证明的那样，用于严重急性呼吸综合征(SARS)感染。作为研制MERS冠状病毒疫苗的初步尝试，我们构建了两个重组腺病毒载体，分别编码MERS-CoV刺突蛋白(S)全长蛋白(Ad5.MERS-S)和S蛋白的S1结构域(Ad5.MERS-S1)，它介导与作为MERS-CoV宿主细胞受体的二肽基肽酶4的结合。以腺病毒为基础的疫苗的安全性和生长特性使其适合临床前试验的MERS-CoV疫苗候选。在过去的15年里，我们展示了腺病毒疫苗平台在激发T和B细胞对所需抗原的特异性反应方面的非凡效率，并参与了有前景的SARS、流感和RSV疫苗的开发。在这里，我们假设皮下(SQ)和/或鼻腔(IN)接种Ad5MERS疫苗将诱导MERS-CoV特异性免疫，这将导致对免疫动物的保护。最终，我们的目标是开发一种针对单峰骆驼的兽用疫苗。我们将通过四个具体目标来验证我们的假设：a)在小鼠模型中测试Ad5.MERS疫苗的免疫原性；b)确定最佳免疫程序和给药途径；c)建立MERS冠状病毒攻击模型；d)确定选定的Ad5.MERS疫苗在没有增强疾病的情况下保护动物免受MERS冠状病毒攻击的能力。

 DESCRIPTION (provided by applicant): Middle East Respiratory Syndrome coronavirus (MERS-CoV) has recently emerged as causative agent of severe respiratory disease in humans. Two hundred and six cases of MERS-CoV infection have been confirmed to date, including 71 deaths. Most infections were geographically linked to the Middle East, but cases also occurred in the UK, Germany, France, Italy and Spain. Dromedary camels are likely the reservoir for MERS-CoV virus. The MERS-CoV spike (S) protein, a characteristic structural component of the viral envelope, is considered a key target of vaccines against coronavirus infection, as we and other have previously demonstrated for severe acute respiratory syndrome (SARS) infection. As an initial attempt to develop a MERS-CoV vaccine, we constructed two recombinant adenoviral vectors encoding the full-length MERS-CoV spike (S) protein (Ad5.MERS-S) and the S1 domain of S protein (Ad5.MERS-S1), which mediates binding to the dipeptidyl peptidase 4, which serves as the host cell receptor of MERS-CoV. The safety profile and the growth characteristics of adenoviral-based vaccines make them suitable MERS-CoV vaccine candidates for preclinical testing. Over the past 15 years, we have demonstrated the extraordinary efficacy of adenoviral vaccine platform in eliciting T and B cell-specific responses to the desired antigens and have been involved in developing promising SARS, influenza and RSV vaccines. Here, we hypothesize that subcutaneous (SQ) and/or intranasal administration (IN) of Ad5.MERS vaccines will elicit MERS-CoV-specific immunity, which will lead to the protection of immunized animals. Ultimately our goal is to develop a veterinary vaccine to target dromedary camels. We will test our hypothesis with four specific aims which will: a) test the immunogenicity of the Ad5.MERS vaccine in a mouse model; b) define the optimal immunization schedule and route of administration; c) establish a MERS-CoV challenge model and d) determine the ability of the selected Ad5.MERS vaccine to protect animal from MERS-CoV challenge in the absence of enhanced disease.