RBD recombinant protein-based SARS vaccine for biodefense

用于生物防御的 RBD 重组蛋白 SARS 疫苗

• 批准号: 8671814
• 负责人: Maria Elena Bottazzi
• 金额: $ 0.39万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-04 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8671814
• 关键词: Adjuvant; Animals; Antibody Formation; Antigen Receptors; Bacteria; Binding; Biochemical; Biological Assay; Blood; Buffers; Categories; Clinical; Clinical Trials; Communicable Diseases; Contractor; Coronavirus; Cyclic GMP; Data; Development; Development Plans; Disease Outbreaks; Disease Outcome; Drug Formulations; Economics; Emergency Situation; Emerging Communicable Diseases; Epitopes; Evaluation; Excipients; Fermentation; Future; Home environment; Human; Immune; Immune response; Immunization; Infection; Institutes; International; Laboratories; Lead; Link; Lipid A; Maryland; Medical; Medicine; Mus; National Institute of Allergy and Infectious Disease; New York; Nonprofit Organizations; Oral Poliovirus Vaccine; Preparation; Prevention; Procedures; Process; Production; Protein S; Proteins; Public Health; Readiness; Recombinant Proteins; Recombinant Vaccines; Recombinants; Regimen; Regulatory Affairs; Reproducibility; Research; Research Institute; Risk; Scientist; Severe Acute Respiratory Syndrome; Solid; Structure; System; TLR4 gene; Techniques; Technology; Technology Transfer; Testing; Texas; TimeLine; Toxicology; Transgenic Mice; Transgenic Model; Translating; Tropical Disease; Universities; Vaccine Antigen; Vaccines; Virus; Yeasts; aluminum sulfate; base; biodefense; cell bank; clinical lot; college; frontier; human disease; immunogenicity; in vivo; innovation; meetings; mouse model; neglect; neutralizing antibody; novel; pandemic disease; pathogen; pre-clinical; prevent; product development; quality assurance; receptor binding; research clinical testing; response; social; tool; vaccine candidate; vaccine efficacy

DESCRIPTION (provided by applicant): The 2002-2003 pandemic of severe acute respiratory syndrome (SARS) posed an enormous threat to global public health and the social and economic stability. Its causative pathogen, the SARS-associated coronavirus (SARS-CoV), has been classified by NIAID as a Category C Priority Pathogen. SARS outbreaks remain a serious concern mainly due to possible zoonotic reintroduction of SARS-CoV into humans, accidental release from a laboratory or deliberate spreading of the virus by a bioterrorist attack. Therefore, an effective and safe vaccine is urgently needed for preventing future SARS outbreaks and for biodefense preparedness. We have identified a highly promising lead candidate vaccine antigen, the receptor binding domain (RBD) of the SARS- CoV spike (S) protein that contains the major neutralizing epitopes and can induce potent neutralizing antibody response and protection in animals against SARS-CoV infection. To rapidly translate our initial proof of concept findings into a solid platform of clinical trials, a consortium of experts was put together consisting of scientists from Baylor College Medicine, the new home of Sabin Vaccine Institute's product development partnership (BCM-Sabin), the New York Blood Center (NYBC) and the University of Texas Medical Branch (UTMB), and in partnership with industrial partners and non-profit organizations. The specific aims of this application are: (1) Expression, purification and pre-clinical characterization of the recombinant RBD (rRBD) protein as a vaccine candidate. The rRBD protein will be expressed in bacteria and yeast expression systems and one of these expression systems will be selected for subsequent studies based on yields, purity, stability, antigenicity, functionality, immunogenicity, and efficacy of the rRBD protein. The immunization regimens will be optimized and the ability of rRBD protein to induce cross-neutralizing antibody response, cross-protection and long-term immune responses and protection will be assessed. (2) Process development, characterization, formulation and stability profiling. A scalable and reproducible fermentation process for rRBD (10 liter scale) and a purification process using chromatographic technologies will be developed. Reproducibility will be confirmed. The specific product quality assays and vaccine formulations with alum and/or glucopyrranosyl lipid A (GLA), an innate adjuvant, will be developed. These assays and procedures will serve the basis for formal lot release and stability evaluation post-manufacturing. (3) Technology transfer, cGMP Manufacture, GLP toxicology and IND Preparation. The cell bank production, production processes and the formulation technology for the rRBD-based SARS vaccine will be transferred to Walter Reed Army Institute of Research (WRAIR) pilot facility for 60-L scale GMP manufacture, formulation and fill and finish. The clinical lots will be released by Sabin- Texas and following a pre-IND meeting with the U.S. FDA, GLP toxicology will be initiated at Frontier Biosciences, a Maryland-based contractor.

描述（由申请人提供）：2002 - 2003年严重急性呼吸综合症（SARS）大流行对全球公共卫生和社会和经济稳定构成了巨大威胁。它的致病病原体，与SARS相关的冠状病毒（SARS-COV），已被NIAID分类为C类优先病原体。 SARS爆发仍然是一个严重的关注，这主要是由于人的人畜共患病重新引入人类，从实验室释放或通过生物恐怖主义攻击而刻意从实验室释放或故意传播病毒。所以， 迫切需要一种有效且安全的疫苗来防止将来的SARS暴发和生物污染物的准备。我们已经确定了一种高度有希望的铅候选疫苗抗原，即SARS-COV尖峰（S）蛋白的受体结合结构域（RBD），其中包含主要中和表位的主要中和表位，并可以诱导动物对SARS-COV感染的有效中和中和抗体反应和保护。要快速将我们最初的概念证明结果转化为临床试验的坚实平台，专家联盟被放在一起 由贝勒学院医学的科学家，萨宾疫苗研究所产品开发合作伙伴关系（BCM-Sabin），纽约血液中心（NYBC）和德克萨斯大学医学分支（UTMB）以及与工业合作伙伴和非营利组织合作的新家。该应用的具体目的是：（1）重组RBD（RRBD）蛋白作为疫苗的表达，纯化和临床前表征。 RRBD蛋白将在细菌和酵母表达系统中表达，这些表达系统之一将根据产量，纯度，稳定性，抗原性，功能，免疫原性和RRBD蛋白的疗效而选择后续研究。将对免疫方案进行优化，并将评估RRBD蛋白诱导交叉中和抗体反应，交叉保护和长期免疫反应和保护的能力。 （2）过程开发，表征，配方和稳定性分析。将开发针对RRBD（10升规模）的可扩展且可再现的发酵过程，并将开发使用色谱技术的纯化过程。可重复性将得到确认。特定的产品质量测定和疫苗配方将开发出天生佐剂的明矾和/或葡萄糖基脂质A（GLA）。这些测定和程序将为制造后的正式释放和稳定评估提供基础。 （3）技术转移，CGMP制造，GLP毒理学和IND制剂。基于RRBD的SARS疫苗的细胞银行生产，生产过程和配方技术将被转移到Walter Reed陆军研究所（WRAIR）试点设施，用于60升规模GMP GMP的制造，配方和填充和填充和填充和填充。临床批次将由德克萨斯州萨宾（Sabin-Texas）发布，并在与美国FDA的预先会议之后，将在马里兰州的承包商Frontier Biosciences启动GLP毒理学。