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（由申请人提供）：中东呼吸综合征冠状病毒（MERS-CoV）最近已成为人类严重呼吸道疾病的病原体，迄今为止已确诊 206 例 MERS-CoV 感染病例，其中 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、意大利和西班牙也发生了病例，单峰骆驼可能是中东呼吸综合征冠状病毒的储存库。 (S) 蛋白是病毒包膜的一种特征结构成分，被认为是抗冠状病毒感染疫苗的关键靶点，正如我们和其他人之前在严重急性呼吸系统综合症 (SARS) 感染方面所证明的那样，作为开发 MERS 的初步尝试。 -CoV疫苗，我们构建了两个重组腺病毒载体，编码全长MERS-CoV刺突（S）蛋白（Ad5.MERS-S）和S蛋白的S1结构域（Ad5.MERS-S1），介导与冠状病毒的结合二肽基肽酶 4，作为 MERS-CoV 的宿主细胞受体，基于腺病毒的疫苗的安全性和生长特性使其成为适合临床前测试的 MERS-CoV 候选疫苗。腺病毒疫苗平台在引发 T 细胞和 B 细胞对所需抗原的特异性反应方面具有非凡功效，并参与了有前景的 SARS、流感和 RSV 疫苗的开发。在这里，我们利用了皮下注射 (SQ) 疫苗。 Ad5.MERS 疫苗和/或鼻内注射 (IN) 将引发 MERS-CoV 特异性免疫力，这将保护免疫动物，最终我们的目标是开发一种针对单峰骆驼的兽用疫苗。具有四个具体目标的假设：a) 在小鼠模型中测试 Ad5.MERS 疫苗的免疫原性；b) 确定最佳免疫计划和给药途径；c) 建立 MERS-CoV 攻击模型； d) 确定所选 Ad5.MERS 疫苗在没有疾病增强的情况下保护动物免受 MERS-CoV 攻击的能力。

项目成果

Microneedle array delivered recombinant coronavirus vaccines: Immunogenicity and rapid translational development.

微针阵列递送重组冠状病毒疫苗：免疫原性和快速转化开发。

• 发表时间: 2020-05
• 影响因子: 11.1
• 作者: Kim, Eun;Erdos, Geza;Huang, Shaohua;Kenniston, Thomas W;Balmert, Stephen C;Carey, Cara Donahue;Raj, V Stalin;Epperly, Michael W;Klimstra, William B;Haagmans, Bart L;Korkmaz, Emrullah;Falo Jr, Louis D;Gambotto, Andrea
• 通讯作者: Gambotto, Andrea