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

 描述（由申请人提供）：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。迄今已确认206例中东呼吸综合征冠状病毒感染，包括71例死亡。大多数感染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-CoV病毒的宿主。MERS-CoV刺突（S）蛋白是病毒包膜的特征性结构成分，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在严重急性呼吸综合征（SARS）感染中所证明的那样。作为开发MERS-CoV疫苗的初步尝试，我们构建了两种重组腺病毒载体，其编码全长MERS-CoV刺突（S）蛋白（Ad 5.MERS-S）和S蛋白的S1结构域（Ad 5.MERS-S1），S蛋白的S1结构域介导与作为MERS-CoV的宿主细胞受体的二肽基肽酶4的结合。腺病毒疫苗的安全性和生长特性使其成为临床前试验的合适MERS-CoV疫苗候选物。在过去的15年里，我们已经证明了腺病毒疫苗平台在引发T和B细胞对所需抗原的特异性应答方面的非凡功效，并参与了开发有前景的SARS、流感和RSV疫苗。在这里，我们假设Ad5.MERS疫苗的皮下（SQ）和/或鼻内给药（IN）将引发MERS-CoV特异性免疫，这将导致免疫动物的保护。我们的最终目标是开发一种针对单峰骆驼的兽用疫苗。我们将用四个具体目标来检验我们的假设，这四个具体目标将：a）在小鼠模型中检验Ad5.MERS疫苗的免疫原性; B）定义最佳免疫接种方案和施用途径; c）建立MERS-CoV攻击模型和d）确定所选Ad5.MERS疫苗在不存在增强疾病的情况下保护动物免受MERS-CoV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.