Plant-derived vaccines against hepatitis C Cooperative *

植物源性丙型肝炎疫苗合作社*

• 批准号: 7489919
• 负责人: Charles Joel Arntzen
• 金额: $ 71.45万
• 依托单位: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7489919
• 关键词: Plant; derived; vaccines; against; hepatitis

DESCRIPTION (provided by applicant): Research in immunology and virology has made enormous progress toward the design of an effective vaccine to prevent Hepatitis C infection, but multidisciplinary efforts are needed to move these designs to the ultimate manufacture of a cost-effective vaccine for global immunization. This proposed Cooperative Research Center (CRC) will critically evaluate a new means to biomanufacture HCV antigens known to induce specific immune responses to HCV - identified through human clinical studies, and predicted to be important in viral clearance - and evaluate responses to these antigens in appropriate in vitro and in vivo model systems. One of the co-Directors of this CRC has lead Chiron's discovery of recombinant antigens from HCV; the evaluation of his currently available suite of proteins in clinical trials indicates that a prophylactic and immunotherapeutic vaccine is feasible. Unfortunately, at least from the standpoint of manufacturing for public health markets, the optimal vaccine should consist of a "cocktail" of multiple antigens to elicit both antibody-mediated and T cell-mediated immune responses. The likely need for two separate protein expression systems to produce this vaccine, one limited by low yields, raises obstacles to commercial development - especially for global use. To overcome these production constraints, this CRC proposes to rapidly utilization current understanding of the properties of important vaccine components to develop and validate a new biomanufacturing system for multiple HCV antigens. A unique feature of this proposed CRC will be the use of green plants as versatile, highly cost-effective production system for recombinant proteins. The research proposed is an interactive partnership that draws upon Chiron's vaccine development expertise to critically evaluate HCV candidate vaccines produced by an academic team that has pioneered the use of plant biotechnology for subunit vaccine manufacture for more than a decade. PROJECT 1: Plant- Derived Envelope Glycoprotein E1/E2 Vaccine for HCV (Mason, H.) PROJECT 1 DESCRIPTION (provided by applicant): Hepatitis C virus (HCV) is a major worldwide agent of acute and chronic hepatitis, with over 3% of the world's population infected and at risk for liver cirrhosis and cancer, and a US cost burden of $1 billion per year. Studies showed that vaccine development should target both antibody and T-cell mediated immunity. Recombinant envelope glycoproteins gpE1 and gpE2 are the leading vaccine candidates for antibody-mediated protection, showing protection in chimpanzee. However, gpE1/gpE2 is currently produced in cultured mammalian cells, with a limited capacity for scale-up to achieve global immunization. Alternatively, production of gpE1/gpE2 in plant systems has the potential for vast scale-up. We hypothesize that: 1) HCV gpE1/gpE2 vaccine can be produced in a plant system in a form that is equivalent to the mammalian cell product used for injection; 2) HCV gpE1/gpE2 vaccine can be scaled up to a commercially competitive level using a leaf or a grain seed-based expression system; and 3) Plant-derived HCV gpE1/gpE2 can stimulate antibody responses when orally delivered by ingestion of minimally processed plant tissue. The specific aims of this proposal will address these questions by using plant-optimized gpE1/gpE2 genes expressed in plants to assess the potential to assemble immunogenic gpE1/gpE2 heterodimers. We will examine tobacco leaf and corn seed expression systems and evaluate gpE1/gpE2 accumulation and quality to select the optimal system. M. Houghton at Chiron Corporation leads their HCV vaccine effort and will direct Project 3 of this HCV Research Center, which will purify gpE1/gpE2 from plant sources and test its immunogenic capacity in animal models. We will furthermore test the potential for use of orally delivered plant-derived gpE1/gpE2 vaccine, with the aim to develop a convenient and economical vaccine for the developing world. If successful, these studies will greatly enhance the capacity to produce an injectable vaccine for HCV, while also offering the possibility to improve worldwide immunization coverage with an oral vaccine.

描述（由申请人提供）：免疫学和病毒学研究在设计预防丙型肝炎感染的有效疫苗方面取得了巨大进展，但需要多学科的努力才能将这些设计转化为最终制造出用于全球免疫的具有成本效益的疫苗。该合作研究中心 (CRC) 将严格评估一种新的生物制造 HCV 抗原的方法，这种抗原已知可诱导对 HCV 的特异性免疫反应（通过人体临床研究确定，并预测对病毒清除很重要），并在适当的体外和体内模型系统中评估对这些抗原的反应。该 CRC 的一位联合主任领导 Chiron 从 HCV 中发现了重组抗原；对他目前在临床试验中可用的蛋白质套件的评估表明，预防性和免疫治疗性疫苗是可行的。不幸的是，至少从公共卫生市场生产的角度来看，最佳疫苗应该由多种抗原的“混合物”组成，以引发抗体介导和 T 细胞介导的免疫反应。生产这种疫苗可能需要两种独立的蛋白质表达系统，其中一种受到产量低的限制，这给商业开发带来了障碍——尤其是全球使用。为了克服这些生产限制，该 CRC 建议快速利用当前对重要疫苗成分特性的了解来开发和验证多种 HCV 抗原的新生物制造系统。该拟议的 CRC 的一个独特特征是使用绿色植物作为重组蛋白的多功能、高成本效益的生产系统。拟议的研究是一种互动合作伙伴关系，利用 Chiron 的疫苗开发专业知识来严格评估由学术团队生产的 HCV 候选疫苗，该学术团队十多年来一直率先使用植物生物技术生产亚单位疫苗。 项目 1：针对 HCV 的植物源包膜糖蛋白 E1/E2 疫苗（Mason, H.） 项目 1 描述（由申请人提供）：丙型肝炎病毒 (HCV) 是全球急性和慢性肝炎的主要病原体，世界上超过 3% 的人口受到感染并面临肝硬化和癌症的风险，美国每年的费用负担为 10 亿美元。 研究表明，疫苗开发应同时针对抗体和 T 细胞介导的免疫。 重组包膜糖蛋白 gpE1 和 gpE2 是抗体介导保护的主要候选疫苗，在黑猩猩中显示出保护作用。 然而，gpE1/gpE2目前是在培养的哺乳动物细胞中产生的，扩大规模以实现全球免疫的能力有限。 或者，在植物系统中生产 gpE1/gpE2 具有大规模扩大规模的潜力。 我们假设：1）HCV gpE1/gpE2 疫苗可以在植物系统中生产，其形式与用于注射的哺乳动物细胞产品相同； 2) 使用基于叶或谷物种子的表达系统，HCV gpE1/gpE2 疫苗可以扩大到商业竞争水平； 3) 植物来源的 HCV gpE1/gpE2 在通过摄入最低限度加工的植物组织口服递送时可以刺激抗体反应。 该提案的具体目标是通过使用植物中表达的植物优化 gpE1/gpE2 基因来评估组装免疫原性 gpE1/gpE2 异二聚体的潜力来解决这些问题。 我们将检查烟叶和玉米种子表达系统，并评估 gpE1/gpE2 积累和质量，以选择最佳系统。 Chiron 公司的 M. Houghton 领导了他们的 HCV 疫苗工作，并将指导该 HCV 研究中心的项目 3，该项目将从植物来源中纯化 gpE1/gpE2 并在动物模型中测试其免疫原性能力。 我们还将进一步测试口服植物源gpE1/gpE2疫苗的使用潜力，旨在为发展中国家开发一种方便且经济的疫苗。 如果成功，这些研究将大大提高生产 HCV 注射疫苗的能力，同时也为提高口服疫苗的全球免疫覆盖率提供了可能性。