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

基于腺病毒的 MERS-CoV 疫苗的临床前评估

• 批准号: 9108846
• 负责人: ANDREA GAMBOTTO
• 金额: $ 20.3万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-10 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9108846
• 关键词: Adenovirus Vector; Adenoviruses; Animal Model; Animals; Antigens; B-Lymphocytes; Binding; Blood group antigen S; Camels; Cessation of life; Characteristics; Chickens; Clinical; Coronavirus; Coronavirus Infections; Development; Dipeptidyl Peptidases; Disease; Dose; Dromedaries; Effectiveness; Equilibrium; Family suidae; France; Germany; Goals; Growth; Health; Human; Immune response; Immunity; Immunization; Immunization Schedule; Immunohistochemistry; In Situ Hybridization; Inbred BALB C Mice; Infection; Influenza; International; Intranasal Administration; Italy; Lead; Length; Link; Lung diseases; Measures; Mediating; Middle East; Middle East Respiratory Syndrome Coronavirus; Modeling; Monitor; Monkeys; Mus; Names; Nose; Organ; Oryctolagus cuniculus; Population; Preclinical Testing; Protein S; Receptor Cell; Recombinant Vaccines; Recombinants; Regimen; Respiratory Syncytial Virus Vaccines; Route; Safety; Severe Acute Respiratory Syndrome; Sheep; Source; Spain; Survival Analysis; Swab; Symptoms; Syndrome; T cell response; T-Lymphocyte; Taxonomy; Testing; Titrations; Vaccinated; Vaccines; Viral; Virulence; Virus; Virus Replication; Virus Shedding; base; efficacy testing; immunogenicity; in vivo; influenza virus vaccine; meetings; mortality; mouse model; neutralizing antibody; novel; particle; pre-clinical; rectal; research clinical testing; respiratory; response; subcutaneous; therapeutic development; vaccine candidate; vaccine development

 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.

 描述（由适用提供）：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犯罪药物。迄今为止，已经确认了26例MERS-COV感染，其中包括71例死亡。大多数感染在地理上与中东有关，但案件也发生在英国，德国，法国，意大利和西班牙。 Dromedary Camels可能是MERS-COV病毒的储层。 MERS-COV尖峰（S）蛋白是病毒包膜的特征结构成分，被认为是针对冠状病毒感染的疫苗的关键靶标，因为我们和其他人先前已经证明了严重的急性呼吸道综合征（SARS）。作为开发MERS-COV疫苗的初步尝试，我们构建了两个编码全长MERS-COV蛋白（S）蛋白（AD5.MERS-S）和S蛋白（AD5.MERS-S1）的S1结构域（AD5.MERS-S1）的重组腺病毒载体（S1），它们介导了与dipeptidyl peptidyl peptide-lepptide-4的宿主相结合的宿主。基于腺病毒的疫苗的安全性和生长特性使其成为合适的MERS-COV疫苗候选临床前测试。在过去的15年中，我们已经证明了腺病毒疫苗平台在引起对所需抗原的T和B细胞特异性反应中的非凡效率，并参与了开发有希望的SARS，actractza和RSV疫苗。在这里，我们假设皮下（平方英尺）和/或鼻内给药（in）的AD5。MERS疫苗将引起MERS-COV特异性的免疫史，这将导致保护免疫抑制的动物。最终，我们的目标是开发一种兽医疫苗来靶向Dromedary Camels。我们将以四个特定目的测试我们的假设：a）在小鼠模型中测试AD5.MERS疫苗的免疫原性； b）定义最佳的免疫抑制时间表和给药途径； c）建立MERS-COV挑战模型，D）确定所选AD5的能力。MERS疫苗在没有增强疾病的情况下保护动物免受MERS-COV挑战的能力。