Preclinical characterization of a multivalent killed Filovirus/Rabies vaccine

多价灭活丝状病毒/狂犬病疫苗的临床前表征

• 批准号: 8790424
• 负责人: Matthias Johannes Schnell
• 金额: $ 120.32万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8790424
• 关键词: Antigens; Attenuated; Biological Assay; CD4 Positive T Lymphocytes; CD8B1 gene; Clinical; Codon Nucleotides; Collaborations; Communicable Diseases; Containment; Cytoplasmic Tail; Data; Democratic Republic of the Congo; Development; Ebola virus; Enzyme-Linked Immunosorbent Assay; Evaluation; Filovirus; Frankfurt-Marburg Syndrome Virus; Genes; Genome; Glycoproteins; Goals; Health; Human; Immune response; Immunity; Immunization; Infection prevention; Laboratories; Licensure; Life; Macaca mulatta; Medical; Molecular; Mus; National Institute of Allergy and Infectious Disease; Pathogenicity; Phase; Phase I Clinical Trials; Preparation; Production; Rabies Vaccines; Rabies virus; Recombinants; Recovery; Research; Resources; Safety; Seeds; Sudan; Sudan Ebola virus; System; Technology; Technology Transfer; Testing; Translational Research; Transmembrane Domain; United States National Institutes of Health; Vaccine Production; Vaccines; Vero Cells; Viral; Viral Vector; Virion; Virus; Virus Diseases; Work; Zaire Ebola virus; base; cell bank; clinical lot; combat; dosage; enzyme linked immunospot assay; experience; immunogenic; immunogenicity; killings; nonhuman primate; novel; particle; pre-clinical; public health emergency; research study; technology development; vaccin protein; vaccination strategy; vaccine candidate; vaccine development; vector; vector vaccine

DESCRIPTION (provided by applicant): HHS Public Health Emergency Medical Countermeasures Enterprise (PHEMCE) indicates the development and acquisition of medical countermeasures for filoviruses as a high priority. However, currently no vaccine candidates against Ebola virus (EBOV) or Marburg virus (MARV) are nearing licensure and the need to develop a safe and efficacious vaccine against filoviruses continues. Whereas several preclinical vaccine candidates against EBOV or MARV exist, their further development is a major challenge based on i) safety concerns, ii) pre-existing vector immunity, and iii) issues such as manufacturing, dosage, and marketability. Here we propose to further develop a new and promising vaccine platform based on chemically inactivated (killed) rabies virus (RABV) virions containing EBOV glycoprotein (GP) in their envelope. Our previous research showed that immunization with such recombinant RABV virions provided excellent protection in mice against lethal challenge with the mouse adapted MA-EBOV and RABV. Moreover, the novel antigen display vehicles are highly immunogenic in non-human primates (NHP). Based on our preliminary results, the goal of this application is to develop, characterize, and extend this nove and promising filovirus vaccine platform. We propose the development and characterization a trivalent filovirus vaccine based on the killed rabies virus virions technology for use in humans t confer protection from all medically relevant filoviruses and RABV. Specifically, two additional vectors containing EBOV Sudan GP or MARV GP will be constructed in addition to the previously developed EBOV Zaire GP containing vaccine. The efficiency of these vaccines against challenge with EBOV, MARV and RABV will be studied in mice, followed by the further testing of EBOV or MARV challenge experiments in NHP. Lastly, we propose to study the required immunogenicity induced by the vaccine vectors for protection from filovirus challenge. The work proposed above toward the further development of our vaccine is performed in parallel with the transfer of the vaccine technology from a laboratory setting to GMP conditions. For this approach, we will adapt the RABV recovery system to Vero cells in a GMP facility, establish a Vero cell bank suitable for production of the vaccine as well as viral seed stocks for the three viral vectors. A production plan for the vaccine has been established, and the final goal of this translational research application is characterization of a trivalent filovirus vaccin and the production of the vaccine in sufficient quantities for a phase I clinical trial. Of note, te further characterization of this vaccine platform will establish the necessary parameters not only for a filovirus vaccine but also the use of this platform for other emerging and reemerging infectious diseases.

描述（由申请人提供）：HHS公共卫生紧急医疗对策企业（PHEMCE）表明，fileoviruss的医疗对策的开发和获取是高优先事项。但是，目前尚无针对埃博拉病毒（EBOV）或马堡病毒（MARV）的候选疫苗候选者接近许可，并且需要继续开发安全有效的疫苗针对FILOVIRES。尽管存在一些针对EBOV或MARV的临床前疫苗候选者，但基于I）安全问题，ii）先前存在的载体免疫以及III）等问题，例如制造，剂量和可销售性。在这里，我们建议基于化学灭活（杀死的）狂犬病病毒（RABV）病毒体进一步开发一个新的疫苗平台，其包膜中含有EBOV糖蛋白（GP）。我们先前的研究表明，这种重组RABV病毒体的免疫在小鼠中为小鼠改编的Ma-ebov和RABV提供了极好的保护，以防止致命挑战。此外，新型的抗原显示车辆在非人类灵长类动物（NHP）中具有高度免疫原性。基于我们的初步结果，该应用程序的目标是开发，表征和扩展这个诺夫和有前途的Filevirus疫苗平台。我们提出了基于杀死的狂犬病病毒病毒技术来用于人类使用的三价丝毒病毒疫苗的开发和表征。具体而言，除了先前开发的Ebov Zaire Zaire GP外，还将构建两个含有Ebov Sudan GP或MARV GP的其他载体。这些疫苗针对EBOV，MARV和RABV挑战的效率将在小鼠中进行研究，然后在NHP中进一步测试EBOV或MARV挑战实验。最后，我们建议研究疫苗向量引起的所需的免疫原性，以防止丝状病毒挑战。上面提出的用于进一步开发疫苗的工作与将疫苗技术从实验室环境转移到GMP条件并行。对于这种方法，我们将使RABV恢复系统适应GMP设施中的Vero细胞，建立适合于三个病毒载体的疫苗生产以及病毒种子库存的Vero细胞库。已经建立了疫苗的生产计划，该翻译研究申请的最终目标是对三价丝状病毒疫苗的表征和I级临床试验的足够数量的疫苗生产。值得注意的是，该疫苗平台的进一步表征将不仅建立用于丝状病毒疫苗的必要参数，而且还将使用该平台用于其他新兴和重新出现的传染病。